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Exposure to chronic light–dark phase shifts during the prepartum nonlactating period attenuates circadian rhythms, decreases blood glucose, and increases milk yield in the subsequent lactation

Open ArchivePublished:January 21, 2020DOI:https://doi.org/10.3168/jds.2019-16980

      ABSTRACT

      Maintaining metabolic balance is a key factor in the health of dairy cattle during the transition from pregnancy to lactation. Little is known regarding the role of the circadian timing system in the regulation of physiological changes during the transition period. We hypothesized that disruption of the cow's circadian timing system by exposure to chronic light–dark phase shifts during the prepartum period would negatively affect the regulation of homeostasis and cause metabolic disturbances, leading to reduced milk production in the subsequent lactation. The objective was to determine the effect of exposure to chronic light–dark phase shift during the last 5 wk prepartum of the nonlactating dry period on core body temperature, melatonin, blood glucose, β-hydroxybutyric acid (BHB) and nonesterified fatty acid (NEFA) concentrations, and milk production. Multiparous cows were moved to tiestalls at 5 wk before expected calving and assigned to control (CTR; n = 16) or phase-shifted (PS; n = 16) treatments. Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to the same photoperiod; however, the light–dark cycle was shifted 6 h every 3 d until parturition. Resting behavior and feed intake were recorded daily. Core body temperature was recorded vaginally for 48 h at 23 and 9 d before expected calving using calibrated data loggers. Blood concentrations of melatonin, glucose, BHB, and NEFA were measured during the pre- and postpartum periods. Milk yield and composition were measured through 60 DIM. Treatment did not affect feed intake or body condition. Cosine fit analysis of 24-h core body temperature and circulating melatonin indicated attenuation of circadian rhythms in the PS treatment compared with the CTR treatment. Phase-shifted cows had lower rest consolidation, as indicated by more total resting time, but shorter resting period durations. Phase-shifted cows had lower blood glucose concentration compared with CTR cows (4 mg/mL decrease), but BHB and NEFA concentrations were similar between PS and CTR cows. Milk yield and milk fat yield were greater in PS compared with CTR cows (2.8 kg/d increase). Thus, exposure to chronic light–dark phase shifts during the prepartum period attenuated circadian rhythms of core body temperature, melatonin, and rest–activity behavior and was associated with increased milk fat and milk yield in the postpartum period despite decreased blood glucose pre- and postpartum. Therefore, less variation in central circadian rhythms may create a more constant milieu that supports the onset of lactogenesis.

      Key words

      INTRODUCTION

      During the transition period, the last 3 wk before calving and the first 3 wk postpartum, major hormonal shifts and metabolic adaptations occur in dairy cows to accommodate the increased energetic demands of fetal growth and the onset of milk production (
      • Bauman D.E.
      • Currie W.B.
      Partitioning of nutrients during pregnancy and lactation: A review of mechanisms involving homeostasis and homeorhesis.
      ;
      • Bell A.W.
      • Bauman D.
      Adaptations of glucose metabolism during pregnancy and lactation.
      ). Successful adaptation to both the onset of lactation and the resulting negative energy balance can provide for a healthy and productive lactation, whereas a poor adaptive response can lead to ketosis, milk fever, and reduced milk production (
      • Duffield T.F.
      • Lissemore K.D.
      • McBride B.W.
      • Leslie K.E.
      Impact of hyperketonemia in early lactation dairy cows on health and production.
      ). Management and environmental conditions, such as photoperiod and heat stress, during the 45- to 60-d dry nonlactating period before parturition can affect the milk production capacity of the cow in the subsequent lactation (
      • Renaudeau D.
      • Quiniou N.
      • Noblet J.
      Effects of exposure to high ambient temperature and dietary protein level on performance of multiparous lactating sows.
      ;
      • Dahl G.E.
      Effects of short day photoperiod on prolactin signaling in dry cows: A common mechanism among tissues and environments?.
      ;
      • Mabjeesh S.J.
      • Sabastian C.
      • Gal-Garber O.
      • Shamay A.
      Effect of photoperiod and heat stress in the third trimester of gestation on milk production and circulating hormones in dairy goats.
      ). Understanding the biological mechanisms that regulate the changes that occur in dairy cattle during the transition period can help in developing farm management approaches that maximize milk production and minimize disease in cows.
      Almost all physiological and behavioral functions of animals are rhythmic, including hormone secretion patterns, sleep–wake cycles, metabolism, and core body temperature. These circadian rhythms (i.e., 24-h cycles of biochemical, physiological, or behavioral processes) evolved as a common strategy among animals to coordinate internal systems and synchronize these systems to the environment (
      • Casey T.M.
      • Plaut K.
      Lactation Biology Symposium: Circadian clocks as mediators of the homeorhetic response to lactation.
      ;
      • Plaut K.
      • Casey T.
      Does the circadian system regulate lactation?.
      ). In mammals, circadian clocks are regulated hierarchically, with the master circadian clock located centrally in the suprachiasmatic nuclei of the hypothalamus. In addition, peripheral clocks are distributed in every organ. Metabolic function and circadian clocks are tightly connected and reciprocally regulated, such that clocks drive metabolic processes and various metabolic parameters affect clocks. Dairy cattle display circadian rhythms of eating behavior; plasma concentrations of metabolic hormones, including insulin, somatotropin, cortisol, melatonin, and triiodothyronine (
      • Dahl G.E.
      • Tao S.
      • Thompson I.M.
      Lactation Biology Symposium: Effects of photoperiod on mammary gland development and lactation.
      ); as well as metabolites, such as plasma glucose, nonesterified fatty acids (NEFA), BHB, and urea nitrogen (
      • Bitman J.
      • Wood D.L.
      • Lefcourt A.M.
      Rhythms in cholesterol, cholesteryl esters, free fatty acids, and triglycerides in blood of lactating dairy cows.
      ;
      • Lefcourt A.M.
      • Huntington J.B.
      • Akers R.M.
      • Wood D.L.
      • Bitman J.
      Circadian and ultradian rhythms of body temperature and peripheral concentrations of insulin and nitrogen in lactating dairy cows.
      ). Photoperiod and feeding behavior affect circadian rhythms of metabolism in cattle (
      • Ogino M.
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      • Yamazaki A.
      • Irimajiri M.
      • Suzuki Y.
      • Kushibiki S.
      • Singu H.
      • Kasuya E.
      • Hasegawa Y.
      • Hodate K.
      Plasma cortisol and prolactin secretion rhythms in cattle under varying external environments and management techniques.
      ), with light–dark information being the most important environmental cue for entraining rhythms established by the master clock in the suprachiasmatic nuclei. Moreover, photoperiod length affects ruminant metabolism and milk production. In particular, exposure to a long-day photoperiod during an established lactation increases milk yield in dairy cattle without initially altering feed intake (
      • Peters R.R.
      • Chapin L.T.
      • Leining K.B.
      • Tucker H.A.
      Supplemental lighting stimulates growth and lactation in cattle.
      ), whereas exposure to a short-day photoperiod during the dry period enhances subsequent lactation performance (
      • Dahl G.E.
      Effects of short day photoperiod on prolactin signaling in dry cows: A common mechanism among tissues and environments?.
      ).
      Human and rodent studies support a mechanistic link between circadian disruption and the development of metabolic diseases (
      • Pillar G.
      • Shehadeh N.
      Abdominal fat and sleep apnea.
      ;
      • Gangwisch J.E.
      Epidemiological evidence for the links between sleep, circadian rhythms and metabolism.
      ;
      • Möller-Levet C.S.
      • Archer S.N.
      • Bucca G.
      • Laing E.E.
      • Slak A.
      • Kabiljo R.
      • Lo J.C.Y.
      • Santhi N.
      • von Schantz M.
      • Smith C.P.
      • Dijk D.-J.
      Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome.
      ). Of particular interest is that metabolism is altered and lactation performance is impaired in mice with mutations in the CLOCK gene, one of the genes that make up the core molecular clocks that generate circadian rhythms of gene expression (
      • Dolatshad H.
      • Campbell E.A.
      • O'Hara L.
      • Maywood E.S.
      • Hastings M.H.
      • Johnson M.H.
      Developmental and reproductive performance in circadian mutant mice.
      ;
      • Hoshino K.
      • Wakatsuki Y.
      • Iigo M.
      • Shibata S.
      Circadian clock mutation in dams disrupts nursing behavior and growth of pups.
      ;
      • Casey T.
      • Crodian J.
      • Suarez-Trujillo A.
      • Erickson E.
      • Weldon B.
      • Crow K.
      • Cummings S.
      • Chen Y.
      • Shamay A.
      • Mabjeesh S.J.
      • Plaut K.
      CLOCK regulates mammary epithelial cell growth and differentiation.
      ). Here our aim was to determine whether the circadian timing system plays a role in maintaining homeostasis and regulating the onset of lactation in transition dairy cows. A common approach to understanding the role of a certain factor in a biological system is to disrupt the factor and determine the consequence to the animal. Environmental cues that function to set the time of circadian clocks are also capable of disrupting clocks when applied at unusual and inappropriate times. Under natural conditions, circadian rhythms are synchronized to the regular 24-h light–dark cycles that are generated by the rotation of Earth. Alterations of natural light–dark cycle timing can disrupt circadian clocks (
      • Papagiannakopoulos T.
      • Bauer M.R.
      • Davidson S.M.
      • Heimann M.
      • Subbaraj L.
      • Bhutkar A.
      • Bartlebaugh J.
      • Vander Heiden M.G.
      • Jacks T.
      Circadian rhythm disruption promotes lung tumorigenesis.
      ;
      • Skinner N.J.
      • Rizwan M.Z.
      • Grattan D.R.
      • Tups A.
      Chronic light cycle-disruption alters central insulin and leptin signalling as well as metabolic markers in male mice.
      ). In this study, a chronic jet-lag model was used to disrupt circadian clocks. In particular, to effectively knock out the function of the circadian timing system, the light–dark cycle to which cows were exposed was shifted by 6 h every 3 d. Previous studies in dairy cows showed that disrupting circadian clocks by exposure to chronic light–dark phase shifts during an established lactation decreased milk production and increased MUN (
      • Casey T.
      • Crodian J.
      • Donkin S.
      • Plaut K.
      Continuously changing light-dark phase decreases milk yield, fat, protein and lactose in dairy cows.
      ). We hypothesized that disruption of the circadian timing system in dairy cows during the nonlactating dry period would decrease their ability to maintain homeostasis during the transition from pregnancy to lactation and cause metabolic disturbances, characterized by increased NEFA and BHB, and be related to decreased milk production. Our study objectives were to determine the effect of exposure to chronic shifts of the light–dark cycle during the last 5 wk of the prepartum nonlactating dry period on (1) circadian rhythms of body temperature and plasma melatonin and behavior (feed intake and activity), (2) blood concentrations of glucose, NEFA, BHB, and insulin, and (3) milk yield and milk composition.

      MATERIALS AND METHODS

      Animal Management, Housing, and Experimental Conditions

      The animal study protocol (protocol no. 1701001523) was reviewed and approved by the Purdue University Institutional Animal Care and Use Committee before beginning the experiments. The study was performed at the Dairy Unit of the Purdue Animal Sciences Research and Education Center in West Lafayette, Indiana. Thirty-two multiparous Holstein cows were matched by parity [2.68 ± 1.19 for control (CTR) and 2.87 ± 1.01 for phase shifted (PS); mean ± SD], previous lactation milk yield (12,578.5 ± 1,685 kg for CTR and 12,864 ± 1,802 kg for PS for 305-d milk), and previous metabolic and mammary-related diseases (ketosis, mastitis, hypocalcemia, metritis, retained placenta, and displaced abomasum) and were assigned to 1 of 2 treatments: CTR (n = 16) or PS (n = 16). Cows were dried off 60 d before expected calving (BEC).
      At 35 d BEC, cows were weighed and BCS were evaluated based on a 1-to-5 scale (
      • Ferguson J.D.
      • Galligan D.T.
      • Thomsen N.
      Principal descriptors of body condition score in Holstein cows.
      ;
      • Roche J.R.
      • Friggens N.C.
      • Kay J.K.
      • Fisher M.W.
      • Stafford K.J.
      • Berry D.P.
      Invited review: Body condition score and its association with dairy cow productivity, health, and welfare.
      ). Mean BW of the CTR cows (755 ± 18.66 kg) was not different from that of PS cows (757 ± 18.62 kg). The BCS of CTR cows (3.53 ± 0.06) was also not different from that of PS cows (3.42 ± 0.06). Following weighing on d 35 BEC, animals were moved to the experimental barn. Cows were housed in individual tiestalls and exposed to photophase treatments (either CTR or PS) in the experimental barn until 3 d BEC (Figure 1). For photophase treatments, CTR cows were exposed to 16 h of light and 8 h of dark, with lights turned on at 0430 h and off at 2030 h. The PS cows were exposed to 16 h of light and 8 h of dark, but the light phase was shifted forward 6 h every 3 d. In the experimental barn, the treatments were separated by a light-proof partition created by double draping fire-retardant tarps from floor to ceiling (Tarps Plus, Abadak Inc., Georgetown, TX). Natural light was eliminated from the barn by covering the windows with light-proof tarp and caulking around the doors. Used for the experiment were bright white light-emitting diode lights (Smart Electrician 5000 lm 46 × 6 LED Tread Plate Shop Light, Menards Inc., Eau Claire, WI), positioned in the experimental barn to provide 150 lx at the animals' eye level. Each cow in the PS treatment was exposed to at least 10 light shifts during the treatment period (35 to 3 d BEC). The temperature in both treatment areas of the experimental barn was the same and varied no more than 5°C (10–15°C) from the start of the experiment (January 25, 2018) to the end (May 28, 2018) of the study. During the prepartum treatment period, animals were released from the tiestalls twice daily at 0430 and 1530 h into a gated holding pen outside the milking parlor for 30 min of exercise.
      Figure thumbnail gr1
      Figure 1Schematic representation of the study design. Thirty-two multiparous Holstein cows were dried off 60 d before expected calving (BEC). On d 35 BEC, animals were moved to the experimental barn and housed in individual tiestalls, and photophase treatments were applied (dashed portion of the arrow) until 3 d BEC. Control cows were exposed to 16 h of light and 8 h of dark, with the lights turned on at 0430 h and off at 2030 h. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, but the light phase was shifted forward 6 h every 3 d. From 3 d BEC to 3 d postparturition (PP), all animals in both treatments were housed in the maternity barn (boxstalls) and exposed to control lighting (16 h of light and 8 h of dark; white portion of the arrow). On d 3 PP, all cows from both treatments were moved back to individual tiestalls, where they were kept until 15 d PP and exposed to control lighting. Then, animals were moved to a freestall barn for the remainder of lactation. Feed intake and resting activity were individually measured from 35 d BEC to 15 DIM. Milk yield was recorded up to 60 DIM. Starting on d 23 and 9 BEC and d 5 PP, blood samples were collected every 4 h during a total of 48 h. Temperature was recorded intravaginally over 48 h on d 23 and 9 BEC.
      At approximately 3 d BEC, the photophase treatments of PS cows were stopped, and all animals were moved to the maternity barn. Cows were exposed to control lighting in the maternity barn and housed in boxstalls for calving until 3 d after parturition. Cows calved 2 ± 3.7 d (mean ± SD) before the expected calving date. Cows that showed signs of parturition before d 3 BEC (11 of the 32 cows) were moved to the maternity barn at the first sign of calving. At 3 DIM, all cows from both treatments were moved back to individual tiestalls until 15 DIM and exposed to control lighting. After 15 DIM, animals were moved to a freestall barn for the remainder of lactation.
      Animals were fed individually for ad libitum intake once daily at 1600 h in the preparturition period and at 1100 h during the postparturition period. Feed was mixed in bulk, and individual daily feed intake was determined from 35 d BEC to 15 DIM by measuring feed offered and refused from the previous day. Cows were fed 110% of the calculated intake of the previous day. From 35 d BEC to parturition, animals were offered a prefresh ration (57.0% DM, 33.2% NDF, 15.8% CP, 39.6% NFC, and 3.9% fatty acids), and after parturition animals were offered a lactation ration (49.9% DM, 28.6% NDF, 15.6% CP, 42.2% NFC, and 5.4% fatty acids; Table 1).
      Table 1Diet ingredients and nutrient composition of prefresh and lactating diets
      ItemPrefreshLactating
      Ingredient
      Soyplus, Landus Cooperative, Ames, IA; LysAAmet, Perdue Agribusiness, Salisbury, MD; QLF Blend 63-38, Quality Liquid Feeds Inc., Dodgeville, MI; Palmit 80, Global Agri-trade Corporation, Rancho Dominguez, CA; Biochlor, Arm and Hammer, Ewing Township, NJ.
      (% of DM)
       Corn silage32.724.6
       Alfalfa silage5.419.1
       Rye hay16.27.8
       Ground corn14.44.8
       High-moisture shell corn17.4
       Soybean meal6.45.5
       Soyplus3.64.8
       Whole fuzzy cottonseed6.0
       Cottonseed hulls6.6
       Distillers grains with solubles0.7
       LysAAMet0.60.8
       QLF Blend 63–382.33.7
       Calcium carbonate1.21.1
       Palmit 801.3
       Biochlor7.0
       Vitamin and mineral mix2.9
      Prefresh vitamin and mineral mix contained 28.55% MegalacR (Church and Dwight Co., Princeton, NJ), 13.25% Diamond V XP (Diamond V, Cedar Rapids, IA), 13.96% magnesium oxide, 9.11% monocalcium phosphate, 8.54% magnesium sulfate, 7.32% salt, 6.68% vitamin E 20,000 IU, 6.07% calcium sulfate, 5.94% mineral premix, 0.43% Rumensin 90 g/lb (40.8 g/kg; Elanco Animal Health, Greenfield, IN), and 0.15% vitamin A 30,000 IU.
      3.1
      Lactating vitamin and mineral mix contained 27.07% sodium bicarbonate, 13.60% salt, 10.89% monocalcium phosphate, 10.72% DCAD Plus (Arm and Hammer), 6.68% Omnigen AF (Phibro Animal Health Corporation, Teaneck, NJ), 6.40% Diamond V XP (Diamond V), 6.59% magnesium oxide, 5.99% calcium sulfate, 5.90% fat yellow grease, 3.38% mineral premix, 1.80% ground corn, 0.78% vitamin E 20,000 IU, and 0.21% Rumensin 90 g/lb (40.8 g/kg; Elanco Animal Health).
      Nutrient composition (% of DM)
       DM57.049.9
       NDF33.228.6
       CP15.815.6
       NFC39.642.2
       Fatty acids3.95.4
      1 Soyplus, Landus Cooperative, Ames, IA; LysAAmet, Perdue Agribusiness, Salisbury, MD; QLF Blend 63-38, Quality Liquid Feeds Inc., Dodgeville, MI; Palmit 80, Global Agri-trade Corporation, Rancho Dominguez, CA; Biochlor, Arm and Hammer, Ewing Township, NJ.
      2 Prefresh vitamin and mineral mix contained 28.55% MegalacR (Church and Dwight Co., Princeton, NJ), 13.25% Diamond V XP (Diamond V, Cedar Rapids, IA), 13.96% magnesium oxide, 9.11% monocalcium phosphate, 8.54% magnesium sulfate, 7.32% salt, 6.68% vitamin E 20,000 IU, 6.07% calcium sulfate, 5.94% mineral premix, 0.43% Rumensin 90 g/lb (40.8 g/kg; Elanco Animal Health, Greenfield, IN), and 0.15% vitamin A 30,000 IU.
      3 Lactating vitamin and mineral mix contained 27.07% sodium bicarbonate, 13.60% salt, 10.89% monocalcium phosphate, 10.72% DCAD Plus (Arm and Hammer), 6.68% Omnigen AF (Phibro Animal Health Corporation, Teaneck, NJ), 6.40% Diamond V XP (Diamond V), 6.59% magnesium oxide, 5.99% calcium sulfate, 5.90% fat yellow grease, 3.38% mineral premix, 1.80% ground corn, 0.78% vitamin E 20,000 IU, and 0.21% Rumensin 90 g/lb (40.8 g/kg; Elanco Animal Health).

      Body Temperature and Resting Behavior Recordings

      Calibrated temperature loggers (iButton DS1921H-F5#, iButtonLink Technology, Baulkham Hills, Australia) were used to measure body temperature (
      • Burfeind O.
      • Suthar V.S.
      • Voigtsberger R.
      • Bonk S.
      • Heuwieser W.
      Validity of prepartum changes in vaginal and rectal temperature to predict calving in dairy cows.
      ,
      • Burfeind O.
      • Suthar V.S.
      • Voigtsberger R.
      • Bonk S.
      • Heuwieser W.
      Body temperature in early postpartum dairy cows.
      ). Each iButton was attached to a blank controlled internal drug release device (EAZI-Breed CIDR Cattle Insert, Zoetis Inc., Parsippany-Troy Hills, NJ). On d 23 and 9 BEC (average of 21 and 7 d before calving ± 3.7 d), starting at 0430 h, iButton controlled internal drug release devices were inserted into the vagina for 48 h and set to record temperature every 30 min (
      • Burdick N.C.
      • Carroll J.A.
      • Dailey J.W.
      • Randel R.D.
      • Falkenberg S.M.
      • Schmidt T.B.
      Development of a self-contained, indwelling vaginal temperature probe for use in cattle research.
      ;
      • Johnson J.S.
      • Shade K.A.
      Characterizing body temperature and activity changes at the onset of estrus in replacement gilts.
      ).
      Following twice-daily exercise, cows were herded through the milking parlor at 0500 h (primarily dark-phase recording for control) and 1600 h (primarily light-phase recording for control) to collect the resting data from individual pedometers (AfiAct II Leg Tag, Afimilk USA Inc., Fitchburg, WI). Pedometers were attached when cows were enrolled into the study at 35 d BEC and were used to record resting bouts (number of bouts), rest duration (average minutes of resting per bout), and total resting time (minutes) up to 15 DIM. To calculate the total daily rest duration, dark- and light-phase recordings were averaged. Daily data for total resting time and resting bouts were calculated as the summation of dark- and light-phase recordings.

      Blood Sampling and Analysis of Glucose, BHB, NEFA, Insulin, and Melatonin

      Blood samples were collected from the coccygeal vein of each cow between 0430 and 0530 h on d 35, 28, and 21 BEC, then every 2 d until 7 d BEC, and then daily until 15 d postparturition (PP). These samples were used to measure circulating glucose, BHB, NEFA, and insulin concentrations. To measure morning versus afternoon differences in blood NEFA levels during the first 9 DIM, plasma was also collected at 1700 h (p.m. sample). A random subset of cows (CTR, n = 6; PS, n = 6) were sampled for temporal analysis of circadian rhythms of NEFA and melatonin. Blood samples were taken from indwelling jugular catheters, inserted without local anesthesia, every 4 h over a 48-h period beginning at 0600 (1.5 h after the start of the light phase in the CTR treatment) at 23 and 9 d BEC and 5 d PP. All blood samples were transferred into EDTA tubes (Becton Dickinson, Rutherford, NJ) and centrifuged at 4°C for 15 min at 2,000 × g immediately following collection. Plasma was transferred to microfuge tubes and stored at −20°C until analysis.
      To measure changes of circulating glucose immediately following parturition, whole blood was sampled from a subset of cows in each treatment (CTR, n = 6; PS, n = 6; first animals added to the study in each treatment) every hour after parturition for 5 h. The blood samples were obtained from the coccygeal vein using a 1-mL syringe.
      Whole-blood glucose and BHB concentrations were measured onsite using a Centrivet system (Acon Laboratories Inc., San Diego, CA) following the manufacturer's directions. Wako NEFA-HR(2) colorimetric assay [Fujifilm Wako Diagnostics USA, Mountain View, CA; intra-assay coefficient of variation (CV) = 3.65%; interassay CV = 5.47%] was used to measure NEFA concentration in plasma samples following the manufacturer's protocol. Plasma insulin was measured using a bovine insulin ELISA Kit (Alpco, Salem, NH; intra-assay CV = 4.07%; interassay CV = 4.12%) following the manufacturer's protocol. Plasma melatonin concentration was determined using liquid chromatography–tandem MS. Briefly, 500 µL of plasma was extracted using acetonitrile (1:4 vol/vol), then vortexed and centrifuged at 3,220 × g at room temperature for 10 min. Supernatant was collected, vacuum-dried, and stored at −80°C until analysis was performed. Chromatography was performed using an Imtakt Intrada amino acid column (3 µm, 2 × 150 mm; (Chrom Tech Inc., Apple Valley, MN) as described and modified (
      • Zhao H.
      • Wang Y.
      • Yuan B.
      • Liu S.
      • Man S.
      • Xu H.
      • Lu X.
      A novel LC-MS/MS assay for the simultaneous determination of melatonin and its two major metabolites, 6-hydroxymelatonin and 6-sulfatoxymelatonin in dog plasma: Application to a pharmacokinetic study.
      ). A standard curve was used to calculate melatonin concentrations (R2 = 0.99).

      Milk Yield and Milk Composition

      Milk yield was recorded twice daily for the first 60 DIM at 0500 and 1600 h using Afifarm software (Afimilk USA Inc.). Milk records and samples were collected daily at the morning (0500 h) and afternoon (1600 h) milkings from 5 to 9 DIM and on d 15, 22, 30, and 60 and were sent to Dairy One (Ithaca, NY), and fat, protein, lactose, and MUN content and SCC were determined using infrared technology (MilkoScan 7RM, Foss, Hillerød, Denmark). Fat, protein, and lactose yields were calculated by multiplying the milk yield on that day by the respective percentage. Somatic cell counts were transformed into log10 scale. Daily milk yield was calculated as the summation between morning and afternoon records. Daily yield of the main milk components (fat, lactose, and protein) was calculated as the multiplication of the component concentration by the milk yield in each milking (a.m. and p.m.) and added by day. Then, the daily concentration of each component was calculated as the component daily yield divided by the yield of milk for the day.

      Data and Statistical Analysis

      Blood glucose, BHB, and NEFA concentration data were adjusted to the actual calving date and collapsed by week relative to parturition. Cosine fit analysis of 24-h rhythms of plasma NEFA and melatonin concentrations and core body temperature was performed with the cosinor package in R (RStudio 1.1.453, Boston, MA). Mesor, amplitude, and acrophase were outputs of the package algorithm and were calculated for each animal and within each 48-h period (at 23 and 9 d BEC for body temperature and at 23 and 9 d BEC and 5 d PP for NEFA and melatonin concentrations). These 3 parameters were used to calculate and visualize the fitted cosine curve for each animal based on the model
      yi = M + A × cos[2π(ti − Aφ)/24],


      where yi is the value of the measured variable at time ti; M is the mean, or mesor, of y throughout a complete cycle; A is the amplitude of the cosine curve on either side of M (half the difference between the highest and the lowest calculated values); and Aφ is the acrophase or phase angle of the maximum value at time ti (time at which the highest value encountered in the cycle occurs). The coefficient of determination (R2) and associated P-values were also calculated for each cow for each sampling period. Mesor, amplitude, and acrophase R2 and P-values were used for statistical analysis. Thus, data presented in tables are means across treatments and not cosine fit of all samples. This approach captures the true variation across animals and the statistical significance of treatment and physiological state effect on fit of data to the 24-h cosine pattern. In contrast, using fitted data from each cow to calculate R2 and P-value overestimates the goodness of fit of data to a 24-h rhythm (i.e., resulted in statically stronger difference). To calculate the area under the curve (AUC), the function area under the curve with spline interpolation in the package MESS (RStudio) was used.
      We used PROC MIXED of SAS (version 9.4; SAS Institute Inc., Cary, NC) to compare mesor, amplitude, acrophase, R2, and P-value between treatments. Tukey-Kramer test was used to evaluate differences in cosine parameters between treatments. Values were considered significant at P < 0.05, and P-values >0.05 but ≤0.1 were discussed as a trend.
      Milk yield, milk composition, blood metabolites (glucose, ketones, and NEFA), feed intake, and resting behavior data were analyzed using PROC MIXED with repeated measure using AR(1) covariance structure in SAS. Rest–activity, blood components, and milk composition data were analyzed using the following model:
      Yijk = μ + Ti + Dj + JDate + (Ti × Dj) + C(T)ik + eijk,


      where Yijk is the dependent variable; μ is the overall mean; Ti is the fixed effect of treatment (i = CTR or PS); Dj is the fixed effect of day of milk (j = 1 to 60); JDate is the covariate of Julian date; Ti × Dj is the interaction between treatment and day of milk; C(T)ik is the random effect of cow nested within treatment; and eijk is the random error. Treatment effects were declared significant at P ≤ 0.05, and trends were declared at P ≤ 0.10. All data were expressed as least squares means and standard errors of the mean.

      RESULTS

      Body Temperature

      The CTR cows exhibited circadian rhythms of core body temperature at 3 and 1 wk BEC, with the acrophase peak occurring just after onset of the dark phase of the light–dark cycle during both sampling periods (2238 h ± 57 min and 2150 h ± 54 min, respectively). A minor peak in body temperature was also evident approximately 2.5 h after the start of a.m. and p.m. exercise (0700 and 1800 h, respectively) in both sampling periods. The R2 of cosinor-fit analysis increased from 3 wk to 1 wk BEC in CTR cows (0.30 ± 0.06 at 23 d BEC and 0.50 ± 0.06 at 9 d BEC; P < 0.05). Mesor and amplitude of body temperature increased between 23 and 9 d BEC in CTR cows (Figure 2; Table 2). The PS animals exhibited a trend (P = 0.1) for circadian rhythmicity of core body temperature during both sampling periods. Similar to CTR cows, the mesor of core body temperature increased between 23 d BEC (39.01 ± 0.07°C) and 9 d BEC (39.26 ± 0.04°C) in PS cows. There was no treatment effect on body temperature mesor. However, unlike in CTR cows, amplitude of body temperature circadian rhythm did not increase in PS cows between 3 and 1 wk BEC. The time of temperature acrophase for PS cattle was similar between 23 and 9 d BEC (0322 h ± 54 min and 0422 h ± 49 min, respectively) and was different from that for CTR cows (P < 0.01). The AUC of core body temperature was not different between periods or treatments.
      Figure thumbnail gr2
      Figure 2Body temperature in nonlactating dairy cows at d 23 and 9 before expected calving (BEC) under (A) the control treatment (exposed to 16 h of light and 8 h of dark) or (B) the phase-shifted treatment (exposed to 16 h of light and 8 h dark, with the photophase shifted 6 h every 3 d). Dashed and solid lines represent d 23 and 9 BEC fitted cosine curves, respectively. Filled symbols = d 23 BEC; empty = d 9 BEC; dots = control cows; squares = phase-shifted cows. Bars under graph A represent the light (white) and dark (black) phases. Dashed bars under graph B represent the shifted photoperiod for phase-shifted cows.
      Table 2Cosine-fit analysis of core body temperature (°C) at 23 and 9 d before expected calving (BEC) in control (CTR; n = 16) and phase-shifted (PS; n = 16) cows
      Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      Time point and treatmentMesor (LSM ± SE)Amplitude
      Difference between mesor and peak, calculated as half the difference between peak and trough.
      (LSM ± SE)
      Acrophase
      Time of the peak, expressed as time of the day (h) ± SE in minutes.
      R2
      Variability explained by the following model: temperature = mesor + ampitude × cos [2π × (hour − acrophase)/24].
      P-value
      Calculated between the observed data and the fitted curve data.
      AUC
      Area under the curve.
      (LSM ± SE)
      23 d BEC
       CTR39.04 ± 0.043
      Values within a column with different superscripts are different (P < 0.05).
      0.15 ± 0.025
      Values within a column with different superscripts are different (P < 0.05).
      2238 ± 15
      Values within a column with different superscripts are different (P < 0.05).
      0.30 ± 0.063
      Values within a column with different superscripts are different (P < 0.05).
      0.011,889.6 ± 11.70
       PS39.01 ± 0.078
      Values within a column with different superscripts are different (P < 0.05).
      0.12 ± 0.023
      Values within a column with different superscripts are different (P < 0.05).
      0322 ± 67
      Values within a column with different superscripts are different (P < 0.05).
      0.26 ± 0.064
      Values within a column with different superscripts are different (P < 0.05).
      0.11,888.6 ± 11.00
      9 d BEC
       CTR39.19 ± 0.076
      Values within a column with different superscripts are different (P < 0.05).
      0.23 ± 0.027
      Values within a column with different superscripts are different (P < 0.05).
      2150 ± 23
      Values within a column with different superscripts are different (P < 0.05).
      0.50 ± 0.062
      Values within a column with different superscripts are different (P < 0.05).
      <0.011,896.2 ± 20.23
       PS39.26 ± 0.041
      Values within a column with different superscripts are different (P < 0.05).
      0.14 ± 0.025
      Values within a column with different superscripts are different (P < 0.05).
      0422 ± 75
      Values within a column with different superscripts are different (P < 0.05).
      0.27 ± 0.067
      Values within a column with different superscripts are different (P < 0.05).
      0.11,896.6 ± 18.46
      a,b Values within a column with different superscripts are different (P < 0.05).
      1 Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      2 Difference between mesor and peak, calculated as half the difference between peak and trough.
      3 Time of the peak, expressed as time of the day (h) ± SE in minutes.
      4 Variability explained by the following model: temperature = mesor + ampitude × cos [2π × (hour − acrophase)/24].
      5 Calculated between the observed data and the fitted curve data.
      6 Area under the curve.

      Melatonin

      Temporal analysis of plasma melatonin concentration rhythms revealed highly similar patterns across the 3 sampling periods (23 and 9 d BEC and 5 d PP; Table 3; Figure 3) in CTR cows. Least squares means of R2 and corresponding P-values across the 3 periods (0.73, 0.78, and 0.77 for 23 d BEC, 9 d BEC, and 5 d PP, respectively) showed a good fit (all P < 0.05) to a 24-h cosine curve. The time of plasma melatonin acrophase (peak) was approximately 3 h after the start of the dark phase in CTR cows. Plasma melatonin concentrations changed dynamically across the day in CTR cows, with low concentration during the light phase and greater concentration during the dark phase (Figure 3), and were reflected by high amplitude values.
      Table 3Cosine-fit analysis of melatonin (pg/mL) at 23 and 9 d before expected calving (BEC) and 5 d postparturition in control (CTR; n = 6) and phase-shifted (PS; n = 6) animals
      Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      Time point and treatmentMesor (LSM ± SE)Amplitude
      Difference between mesor and peak, calculated as half the difference between peak and trough.
      (LSM ± SE)
      Acrophase
      Time of the peak, expressed as time of the day (h) ± SE in minutes.
      R2
      Variability explained by the following model: temperature = mesor + ampitude × cos [2π × (hour − acrophase)/24].
      P-value
      Calculated between the observed data and the fitted curve data.
      AUC
      Area under the curve.
      (LSM ± SE)
      23 d BEC
       CTR31.42 ± 3.05332.66 ± 4.5730010 ± 170.73 ± 0.025
      Values with different superscripts are different (P < 0.05) between treatments or time points.
      <0.011,522.25 ± 174.687
       PS42.01 ± 8.56835.10 ± 8.6590112 ± 1590.79 ± 0.031
      Values with different superscripts are different (P < 0.05) between treatments or time points.
      <0.011,938.09 ± 322.403
      9 d BEC
       CTR31.71 ± 2.83532.68 ± 5.7680006 ± 250.78 ± 0.025
      Values with different superscripts are different (P < 0.05) between treatments or time points.
      <0.011,511.34 ± 160.512
       PS42.47 ± 7.21932.94 ± 6.5460026 ± 1700.55 ± 0.065
      Values with different superscripts are different (P < 0.05) between treatments or time points.
      0.062,085.53 ± 384.394
      5 d PP
       CTR35.72 ± 4.57241.18 ± 8.3220000 ± 210.77 ± 0.018
      Values with different superscripts are different (P < 0.05) between treatments or time points.
      <0.011,811.72 ± 247.085
       PS39.31 ± 7.84534.64 ± 11.1330241 ± 1600.60 ± 0.112
      Values with different superscripts are different (P < 0.05) between treatments or time points.
      0.081,936.81 ± 386.014
      a,b Values with different superscripts are different (P < 0.05) between treatments or time points.
      1 Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      2 Difference between mesor and peak, calculated as half the difference between peak and trough.
      3 Time of the peak, expressed as time of the day (h) ± SE in minutes.
      4 Variability explained by the following model: temperature = mesor + ampitude × cos [2π × (hour − acrophase)/24].
      5 Calculated between the observed data and the fitted curve data.
      6 Area under the curve.
      Figure thumbnail gr3
      Figure 3Melatonin concentration (pg/mL) in periparturient dairy cows at d 23 and 9 before expected calving (BEC) and d 5 postparturition (PP). Graphs show melatonin concentration of plasma samples collected every 4 h across 48 h from (top row) cows in the control treatment (exposed to 16 h of light and 8 h of dark; n = 6) at (A) d 23 BEC, (B) d 9 BEC, and (C) d 5 PP and (bottom row) cows in the phase-shifted treatment (exposed to 16 h of light and 8 h of dark, with the photophase shifted 6 h every 3 d; n = 6) at (D) d 23 BEC, (E) d 9 BEC, and (F) d 5 PP. Different shapes represent individual cows used in the study. Bars under graphs in panels A, B, and C represent the light (white) and dark (black) phases. Dashed bars under graphs in panels D, E, and F represent the light–dark phase shifts.
      Cosine fit analysis of plasma melatonin concentration found that PS cows fit 24-h rhythms only at 3 wk BEC (Figure 3; Table 3). The time of peak melatonin was not different between treatments, but the acrophase standard errors showed greater variation in PS cows. There was a trend for an overall effect of treatment on melatonin mesor (32.95 ± 0.35 and 41.27 ± 2.72 pg/mL for CTR and PS, respectively; P = 0.08) and AUC (1,615.10 ± 194.10 and 1,986.81 ± 352.27 for CTR and PS, respectively; P = 0.09).

      Feed Intake and Rest–Activity

      Treatment did not affect DMI (16.52 ± 0.331 and 16.24 ± 0.339 kg/d for CTR and PS, respectively; P = 0.56; Supplemental Figure S1, https://doi.org/10.3168/jds.2019-16980). Feed intake was greater in the postpartum period than in the prepartum period in both treatments (P < 0.01; 15.70 ± 0.422 and 15.48 ± 0.423 kg/d for CTR and PS, respectively, in the prepartum period; 18.67 ± 0.558 and 18.321 ± 0.615 kg/d for CTR and PS, respectively, in the postpartum period).
      Total resting time was greater during the prepartum period than during the postpartum period (Supplemental Figure S2, https://doi.org/10.3168/jds.2019-16980). The PS cows rested more each day than the CTR cows (649.95 ± 11.87 and 700.14 ± 12.33 min for CTR and PS, respectively; P < 0.01; Table 4). Treatment by day analysis showed that the main differences in rest–activity were in the preparturition period (Supplemental Figure S2). Diurnal differences in total rest time were evident for both treatments, with dark phase (1600–0500 h) resting time being greater (P < 0.01) than light phase (0500–1600 h) resting time. Number of rest bouts was greater (P < 0.01) in the dark-phase recording than in the light-phase recording for both treatments. Number of rest bouts across a day was greater in PS cow (10.21 ± 0.38 and 11.76 ± 0.39 for CTR and PS, respectively; P < 0.01), with multiple treatment by day differences evident in the preparturition period (Supplemental Figure S3, https://doi.org/10.3168/jds.2019-16980). The PS cows had fewer minutes of rest duration per bout than the CTR cows (67.65 ± 1.41 and 61.83 ± 1.48 min in CTR and PS, respectively; P < 0.01), and this effect was more pronounced in the preparturition treatment period (Supplemental Figure S4, https://doi.org/10.3168/jds.2019-16980).
      Table 4Daily light period (L
      Light phase data were collected at 1600 h and represent data recorded from 0500 to 1600 h (the primary dark phase in CTR cows).
      ) and dark period (D
      Dark phase data were collected at 0500 h and represent resting data recorded from 1600 to 0500 h (the primary light phase in CTR cows).
      ) resting bouts (RB), resting duration (RD), and resting time (RT) in control (CTR) and phase-shifted (PS) dairy cows
      Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      ItemCTRPSSEM
      Largest SE among treatments.
      P-valueCTRPS
      LDSEM
      Largest SE among treatments.
      P-valueLDSEM
      Largest SE among treatments.
      P-value
      RB (no. of bouts)10.2111.760.395<0.014.855.670.102<0.015.726.520.164<0.01
      RD (min/bout)67.6561.831.482<0.0170.3765.801.3460.0262.0161.901.5750.96
      RT (min)649.95700.1412.333<0.01306.31341.444.593<0.01321.02359.845.919<0.01
      1 Light phase data were collected at 1600 h and represent data recorded from 0500 to 1600 h (the primary dark phase in CTR cows).
      2 Dark phase data were collected at 0500 h and represent resting data recorded from 1600 to 0500 h (the primary light phase in CTR cows).
      3 Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      4 Largest SE among treatments.

      Blood Glucose, Ketones, NEFA, and Insulin

      Mean blood glucose concentrations were greater in the pre- versus postparturition sampling periods for both CTR cows (78.52 ± 0.39 and 68.00 ± 0.75 mg/dL in pre- and postparturition, respectively) and PS cows (73.90 ± 0.51 and 62.81 ± 0.61 mg/dL in pre- and postparturition, respectively; Figure 4A). Treatment had an overall effect (P < 0.05) on blood glucose, with PS cows having lower glucose than CTR cows (73.06 ± 0.64 and 69.61 ± 0.61 mg/dL for CTR and PS, respectively). Treatment by week analysis revealed differences between treatments at 2 wk before and 2 wk after parturition. Analysis of blood glucose concentration in the hours immediately after parturition found lower concentrations in PS animals compared with CTR animals (Figure 4B). In both treatments, the peak of glucose concentration occurred between 1 and 2 h postparturition.
      Figure thumbnail gr4
      Figure 4Blood glucose, BHB, and nonesterified fatty acid (NEFA) concentrations in the periparturient period in dairy cattle in the control treatment (exposed to 16 h of light and 8 h of dark; n = 16; black bars) or the phase-shifted treatment (exposed to 16 h of light and 8 h of dark, with the photophase shifted 6 h every 3 d; n = 16; dashed bars). (A) Weekly blood glucose concentration (mg/dL) in control and phase-shifted cows. (B) Blood glucose concentration (mg/dL) after parturition in a subset of control (n = 6) and phase-shifted (n = 6) cows. (C) Weekly blood BHB concentration (mmol/dL) in control and phase-shifted cows. (D) Weekly plasma NEFA concentration (mEq/L) in control and phase-shifted cows. Asterisks represent treatment by week or hour effect (P < 0.05). Data are presented as LSM ± SEM.
      Physiological state had a significant effect on BHB and NEFA concentrations, with concentrations being greater in the postpartum period than in the prepartum period (Figure 4C and D, respectively). There was no effect of treatment on BHB or NEFA metabolites in blood at the 0600 h sampling. Cosinor analysis of plasma NEFA concentrations found no significant evidence for circadian rhythms at 23 d BEC, 9 d BEC, and 5 d PP in either treatment (P > 0.05; Figure 5). The NEFA concentration was greater in the morning than in the afternoon in both treatments (P = 0.03; 0.72 ± 0.09 and 0.48 ± 0.08 mEq/mL in CTR a.m. and p.m., respectively; 0.89 ± 0.08 and 0.69 ± 0.08 mEq/mL in PS a.m. and p.m., respectively; Figure 6). The PS cows tended (P = 0.06) to have greater NEFA concentrations during the first 9 d of lactation (0.59 ± 0.07 and 0.79 ± 0.06 for CTR and PS, respectively).
      Figure thumbnail gr5
      Figure 5Nonesterified fatty acid (NEFA) plasma concentration (mEq/L) in periparturient dairy cows at d 23 and 9 before expected calving (BEC) and d 5 postparturition (PP). Graphs show NEFA concentration measured in plasma collected every 4 h across 48 h from (top row) cows in the control treatment (exposed to 16 h of light and 8 h of dark) at (A) d 23 BEC, (B) d 9 BEC, and (C) d 5 PP and (bottom row) cows in the phase-shifted treatment (exposed to 16 h of light and 8 h of dark, with the photophase shifted 6 h every 3 d) at (D) d 23 BEC, (E) d 9 BEC, and (F) d 5 PP. Bars under graphs in panels A, B, and C represent the light (white) and dark (black) phases. Dashed bars under graphs in panels D, E, and F represent the shifted photophase to which phase-shifted cows were exposed.
      Figure thumbnail gr6
      Figure 6Morning (solid lines) and afternoon (dashed lines) blood nonesterified fatty acid (NEFA) concentrations during the first 9 DIM in 32 dairy cows in the control treatment (exposed to 16 h of light and 8 h of dark; ●) or the phase-shifted treatment (exposed to 16 h of light and 8 h of dark, with the photophase shifted 6 h every 3 d; ■) during the preparturient period. Data are presented as LSM.
      Treatment did not have an overall effect on insulin concentration, but on day of calving, CTR cows had greater insulin concentration than PS cows (Figure 7). Physiological state affected insulin concentration in both treatments (P < 0.05), with greater concentrations in the prepartum versus postpartum period.
      Figure thumbnail gr7
      Figure 7Plasma insulin in periparturient dairy cows. Multiparous dairy cows (n = 32) were assigned to either the control treatment (exposed to 16 h of light and 8 h of dark; n = 16; solid line) or the phase-shifted treatment (exposed to 16 h of light and 8 h of dark, with the photophase shifted 6 h every 3 d; n = 16; dashed line) and sampled on d 35, 21, and 2 before calving and d 0, 2, 5, 9, 15, and 21 postparturition. Data are presented as LSM ± SEM.

      Milk Yield and Composition

      There was an overall treatment effect on milk yield to 60 DIM. The PS cows produced an average of 2.8 kg/d more milk than the CTR cows (Table 5; Figure 8). Although there were no differences in percent fat, protein, or lactose between treatments, daily yield of fat was 220 g/d greater in PS cows (P = 0.02). Milk urea nitrogen and SCC were not different between treatments.
      Table 5Daily milk production (d 1–60) and milk composition (d 5–9, 15, 22, 30, and 60) of cows exposed to the control (CTR) and phase-shifted (PS) treatments during the nonlactating period
      ItemTreatment
      Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      SEM
      Largest SE among treatments.
      P-value
      CTRPS
      Milk yield
      Daily milk yield from d 1 to 60 postparturition.
      (kg/d)
      40.3043.100.9950.05
      Milk fat yield (kg/d)1.671.890.0610.02
      Milk fat (%)4.704.890.1270.30
      Milk protein yield (kg/d)1.121.190.0430.24
      Milk protein (%)3.103.070.0370.55
      Milk lactose yield (kg/d)1.701.830.0660.18
      Milk lactose (%)4.624.630.0360.87
      MUN (mg/dL)8.378.290.2390.86
      SCC (log10)4.794.700.0490.21
      1 Control cows were exposed to 16 h of light and 8 h of dark. Phase-shifted cows were exposed to 16 h of light and 8 h of dark, and the photophase was shifted 6 h every 3 d.
      2 Largest SE among treatments.
      3 Daily milk yield from d 1 to 60 postparturition.
      Figure thumbnail gr8
      Figure 8Milk yield of dairy cows exposed to the control treatment (exposed to 16 h of light and 8 h of dark; solid line) or the phase-shifted treatment (exposed to 16 h of light and 8 h of dark, with the photophase shifted 6 h every 3 d; dashed line) from 5 wk prepartum to 3 d before parturition. Data were recorded up to 60 DIM and are expressed as LSM ± SEM.

      DISCUSSION

      Exposing dairy cows to chronic light–dark phase shifts beginning 5 wk BEC to parturition attenuated rhythms of 2 primary master clock outputs (body temperature and melatonin concentration). However, the experimental manipulation did not have detrimental effects on metabolism or milk production as hypothesized. In fact, the light–dark phase shift treatment increased milk yield up to 60 DIM, suggesting that a more constant daily milieu of hormones and metabolites may be conducive for lactogenesis.

      Circadian Disruption Changed Rhythms of Body Temperature, Melatonin, and Resting Behavior

      Core body temperature and melatonin serve as indicators of suprachiasmatic nuclei function (
      • Mohawk J.A.
      • Green C.B.
      • Takahashi J.S.
      Central and peripheral circadian clocks in mammals.
      ). Differences in the circadian rhythms of body temperature and melatonin between treatments suggested that the continuous light–dark cycle phase shifting affected the master clock. The acrophase of PS cows was shifted 5 to 6 h relative to CTR cows. Peak of core body temperature (acrophase) was approximately 2 h after initiation of the dark phase in the CTR treatment, which was similar to findings of others (
      • Burfeind O.
      • Suthar V.S.
      • Voigtsberger R.
      • Bonk S.
      • Heuwieser W.
      Validity of prepartum changes in vaginal and rectal temperature to predict calving in dairy cows.
      ,
      • Burfeind O.
      • Suthar V.S.
      • Voigtsberger R.
      • Bonk S.
      • Heuwieser W.
      Body temperature in early postpartum dairy cows.
      ), whereas the time of core body temperature peak (acrophase) in PS cattle was 0322 and 0422 h for 23 and 9 d BEC, respectively. The shift in timing of PS temperature rhythms likely reflected adjustment of the circadian timing system to other reliable, regularly occurring cues, which in the present study was time of first daily exercise at 0430 h.
      In CTR cows, a significant increase in core body temperature amplitude and mesor occurred between 3 and 1 wk BEC. The increase in mesor was likely related to thermogenesis associated with the progression of pregnancy and fetal growth (
      • Schrader J.A.
      • Walaszczyk E.J.
      • Smale L.
      Changing patterns of daily rhythmicity across reproductive states in diurnal female Nile grass rats (Arvicanthis niloticus).
      ;
      • Gamo Y.
      • Troup C.
      • Mitchell S.E.
      • Hambly C.
      • Vaanholt L.M.
      • Speakman J.R.
      Limits to sustained energy intake. XX. Body temperatures and physical activity of female mice during lactation.
      ). Similar to CTR cows, mesor of core body temperature of PS cows increased from 23 to 9 d BEC. Increase in core body temperature between 23 and 9 d BEC was accompanied by an increase in circadian rhythm amplitude in CTR cows. However, no increase in body temperature rhythm amplitude occurred between 9 and 23 d BEC in PS cows. The amplitude reflects the degree of fluctuation of the circadian rhythm and is the difference between mesor and peak. There was a 0.5°C difference in peak and trough of core body temperature in CTR cows, whereas the difference in peak and trough of core body temperature range was 0.3°C for PS cows. This finding supports a dampening or attenuation of rhythms in the PS treatment relative to the CTR treatment.
      Melatonin synthesis is inhibited by light, and changes in circadian rhythms of plasma melatonin reflect this response in CTR cows, with levels being almost undetectable during the light phase. The increased mesor and greater AUC of melatonin in PS versus CTR cows supports that PS cows had greater daily exposure to melatonin. The increase in milk yield due to exposure to a short-day photoperiod during the nonlactating dry period is also associated with greater circulating melatonin levels (
      • Velasco J.M.
      • Reid E.D.
      • Fried K.K.
      • Gressley T.F.
      • Wallace R.L.
      • Dahl G.E.
      Short-day photoperiod increases milk yield in cows with a reduced dry period length.
      ;
      • Dahl G.E.
      • Tao S.
      • Thompson I.M.
      Lactation Biology Symposium: Effects of photoperiod on mammary gland development and lactation.
      ), suggesting that there may be a relationship between melatonin concentrations and milk yield. However, feeding melatonin to increase plasma concentrations did not increase milk yield (
      • Lacasse P.
      • Vinet C.M.
      • Petitclerc D.
      Effect of prepartum photoperiod and melatonin feeding on milk production and prolactin concentration in dairy heifers and cows.
      ). Thus, greater melatonin in PS alone may not account for the increased milk yield.
      Cattle in both treatments had greater total resting time and rest durations per bout in the prepartum versus postpartum periods. This is consistent with findings of others, who reported that the reduction in resting time in the postpartum versus prepartum period is due to increased time spent eating and in the milking parlor (
      • Kaufman E.I.
      • LeBlanc S.J.
      • McBride B.W.
      • Duffield T.F.
      • DeVries T.J.
      Short communication: Association of lying behavior and subclinical ketosis in transition dairy cows.
      ). The PS treatment affected behavior, with differences between treatments in total rest time, number of rest bouts, and duration of rest bouts in the preparturition period. The increase in number of bouts but decrease in resting bout duration suggests less consolidation of resting in a 24-h rest–activity cycle. There were no differences between treatments in rest variables in the postparturition period, and so changes in PS treatment behavior were likely a direct effect of light–dark phase shifts and thus consistent with disruption of the circadian timing system preparturition.

      Circadian Disruption During Preparturition Decreased Blood Glucose Pre- and Postparturition

      Blood glucose decreased from pregnancy to lactation in both treatments, and these changes are consistent with previous findings (
      • Reverchon M.
      • Ramé C.
      • Cognié J.
      • Briant E.
      • Elis S.
      • Guillaume D.
      • Dupont J.
      Resistin in dairy cows: Plasma concentrations during early lactation, expression and potential role in adipose tissue.
      ;
      • Hernández-Castellano L.E.
      • Hernandez L.L.
      • Weaver S.
      • Bruckmaier R.M.
      Increased serum serotonin improves parturient calcium homeostasis in dairy cows.
      ;
      • Ruoff J.
      • Borchardt S.
      • Heuwieser W.
      Short communication: Associations between blood glucose concentration, onset of hyperketonemia, and milk production in early lactation dairy cows.
      ). The decrease in circulating glucose concentrations likely reflects the increased demand for glucose by the lactating mammary gland, which increases 2.5-fold over the gravid uterus in late pregnancy (
      • Bell A.W.
      • Bauman D.
      Adaptations of glucose metabolism during pregnancy and lactation.
      ).
      Blood glucose was reduced in PS cows relative to CTR cows during the last 2 wk of pregnancy and the first 2 wk after calving. Lower blood glucose concentrations were not accompanied by increased mobilization of fat reserves based on the lack of differences in NEFA and BHB concentration between CTR and PS cows. In dairy cows, increased glucose requirements during late pregnancy and lactation are met in part by decreased uptake of glucose by adipose tissue, skeletal muscle, and other tissues through a temporary increase of peripheral insulin resistance (
      • Bell A.W.
      • Bauman D.
      Adaptations of glucose metabolism during pregnancy and lactation.
      ;
      • De Koster J.D.
      • Opsomer G.
      Insulin resistance in dairy cows.
      ). Thus, PS treatment may have diminished changes that lead to peripheral insulin resistance and allowed greater uptake of glucose from circulating pools by peripheral tissues before parturition. During lactation, the lower glucose concentration in PS cows may be due to their higher milk production and thus a greater requirement for glucose. Previous studies in humans and rodents showed that the disruption of the circadian timing system induced hyperglycemia and insulin resistance (
      • Froy O.
      The relationship between nutrition and circadian rhythms in mammals.
      ;
      • Shi S.Q.
      • Ansari T.S.
      • McGuinness O.P.
      • Wasserman D.H.
      • Johnson C.H.
      Circadian disruption leads to insulin resistance and obesity.
      ;
      • Qian J.
      • Scheer F.A.J.L.
      Circadian system and glucose metabolism: Implications for physiology and disease. Trends in endocrinology and metabolism.
      ). However, circadian disruption of nonpregnant ewes using a rotating shift-work model that inverted feeding time with a 12-h shift in light–dark phase resulted in hypoglycemia with no effect on insulin sensitivity (
      • Varcoe T.J.
      • Gatford K.L.
      • Voultsios A.
      • Salkeld M.D.
      • Boden M.J.
      • Rattanatray L.
      • Kennaway D.J.
      Rapidly alternating photoperiods disrupt central and peripheral rhythmicity and decrease plasma glucose, but do not affect glucose tolerance or insulin secretion in sheep.
      ). However, when the same research group exposed pregnant ewes to the shift-work paradigm, hyperglycemia and insulin resistance ensued in a subset of animals (
      • Gatford K.L.
      • Kennaway D.J.
      • Liu H.
      • Kleemann D.O.
      • Kuchel T.R.
      • Varcoe T.J.
      Simulated shift work disrupts maternal circadian rhythms and metabolism, and increases gestation length in sheep.
      ). In ruminants, the main source of glucose is from gluconeogenesis in the liver, whereas in monogastric animals circulating glucose is reflected in dietary intake. The contrasting findings in glycemic index suggest that monogastrics and ruminants respond to circadian system disruption differently. However, tissue-specific deletion of BMAL1 core clock gene in the liver resulted in disturbances in glucose metabolism associated with hypoglycemia (
      • Lamia K.A.
      • Storch K.-F.
      • Weitz C.J.
      Physiological significance of a peripheral tissue circadian clock.
      ), and so the resulting changes in glucose may depend on the model system used to determine the role of the circadian timing system in the regulation of physiology.

      NEFA Did Not Show Circadian Rhythms in Blood but Showed Diurnal Variations in Both Treatments in Early Lactation

      Temporal analysis of NEFA blood concentrations did not reveal circadian rhythms at any of the 3 sampling periods (23 d BEC, 9 d BEC, and 5 d PP). However, differences in NEFA concentrations were found in approximately 12-h intervals of a.m. and p.m. samples taken the first 9 DIM. Nutrition influences concentration of blood metabolites, with eating pattern (times and duration of intake, rumination, and fasting) affecting circulating nutrients. Lack of a circadian rhythm in NEFA has also been reported for mid-lactation cows despite evidence for rhythms in plasma glucose, BUN, and insulin (
      • Niu M.
      • Ying Y.
      • Bartell P.A.
      • Harvatine K.J.
      The effects of feeding rations that differ in fiber and fermentable starch within a day on milk production and the daily rhythm of feed intake and plasma hormones and metabolites in dairy cows.
      ;
      • Niu M.
      • Harvatine K.J.
      The effects of feeding a partial mixed ration plus a top-dress before feeding on milk production and the daily rhythm of feed intake and plasma hormones and metabolites in dairy cows.
      ). However, when timing of feed dispersal was limited, circadian rhythms of NEFA were revealed in lactating dairy cows and were affected by time of day cows were fed (
      • Niu M.
      • Ying Y.
      • Bartell P.A.
      • Harvatine K.J.
      The effects of feeding time on milk production, total-tract digestibility, and daily rhythms of feeding behavior and plasma metabolites and hormones in dairy cows.
      ). A study of mid-lactation dairy cows (
      • Bitman J.
      • Wood D.L.
      • Lefcourt A.M.
      Rhythms in cholesterol, cholesteryl esters, free fatty acids, and triglycerides in blood of lactating dairy cows.
      ) found spikes in circulating free fatty acids every 2 to 3 h, which was correlated with balancing between the entry and removal of lipids from the blood stream. Together, these findings suggest that circulating NEFA concentrations may primarily reflect demand and feeding behavior rather than be driven by circadian clocks. Further studies are needed to better understand blood NEFA regulation.

      Circadian Disruption During Preparturition Increased Milk and Milk Fat Yields

      Milk yield is determined by the number and metabolic activity of mammary epithelial cells. The mammary gland undergoes significant remodeling during the nonlactating dry period, including the replenishment of secretory epithelium (
      • Sordillo L.M.
      • Nickerson S.C.
      Morphologic changes in the bovine mammary gland during involution and lactogenesis.
      ;
      • Capuco A.V.
      • Akers R.M.
      • Smith J.J.
      Mammary growth in Holstein cows during the dry period: Quantification of nucleic acids and histology.
      ;
      • De Vries L.D.
      • Dover H.
      • Casey T.
      • VandeHaar M.J.
      • Plaut K.
      Characterization of mammary stromal remodeling during the dry period.
      ). Varying exposures to differing management and environmental factors, such as photoperiod and heat stress, during the nonlactating dry period affect the number and metabolic activity of the secretory epithelium and thus the milk production capacity of the cow (
      • Dahl G.E.
      Effects of short day photoperiod on prolactin signaling in dry cows: A common mechanism among tissues and environments?.
      ;
      • do Amaral B.C.
      • Connor E.E.
      • Tao S.
      • Hayen J.
      • Bubolz J.
      • Dahl G.E.
      Heat-stress abatement during the dry period: Does cooling improve transition into lactation?.
      ;
      • Mabjeesh S.J.
      • Sabastian C.
      • Gal-Garber O.
      • Shamay A.
      Effect of photoperiod and heat stress in the third trimester of gestation on milk production and circulating hormones in dairy goats.
      ). The magnitude of increase in milk yield in the PS treatment versus the CTR treatment was similar to what is reported for cattle exposed to short-day versus long-day photoperiod during the nonlactating dry period (
      • Dahl G.E.
      Effects of short day photoperiod on prolactin signaling in dry cows: A common mechanism among tissues and environments?.
      ). A short-day photoperiod during the nonlactating dry period increased expression of genes that regulate proliferation and differentiation of cells in the mammary gland (
      • Bentley P.A.
      • Wall E.H.
      • Dahl G.E.
      • McFadden T.B.
      Responses of the mammary transcriptome of dairy cows to altered photoperiod during late gestation.
      ); it also attenuated rhythms of expression of core clock genes in mammary tissue of goats (
      • Casey T.M.
      • Plaut K.
      • Kalyesubula M.
      • Shamay A.
      • Sabastian C.
      • Wein Y.
      • Bar-Shira E.
      • Reicher N.
      • Mabjeesh S.J.
      Mammary core clock gene expression is impacted by photoperiod exposure during the dry period in goats.
      ). Our work in cells and rodents supports a role for the circadian clocks in regulation of mammary epithelial growth and differentiation (
      • Casey T.
      • Crodian J.
      • Suarez-Trujillo A.
      • Erickson E.
      • Weldon B.
      • Crow K.
      • Cummings S.
      • Chen Y.
      • Shamay A.
      • Mabjeesh S.J.
      • Plaut K.
      CLOCK regulates mammary epithelial cell growth and differentiation.
      ). Thus, it is possible that attenuation of circadian rhythms in the PS treatment affected mammary-specific clocks in a manner that increased proliferation of the mammary tissue preparturition and is reflected as an increase in milk yield during lactation.
      Feed intake was reduced around parturition and recovered to levels greater than the prepartum period over the first 2 wk after calving in both treatments. This pattern of feed intake was expected and consistent with previous studies of transition-period cows (
      • Fairfield A.M.
      • Plaizier J.C.
      • Duffield T.F.
      • Lindinger M.I.
      • Bagg R.
      • Dick P.
      • McBride B.W.
      Effects of prepartum administration of a monensin controlled release capsule on rumen pH, feed intake, and milk production of transition dairy cows.
      ;
      • Shi W.
      • Knoblock C.E.
      • Murphy K.V.
      • Bruinjé T.C.
      • Yoon I.
      • Ambrose D.J.
      • Oba M.
      Effects of supplementing a Saccharomyces cerevisiae fermentation product during the periparturient period on performance of dairy cows fed fresh diets differing in starch content.
      ). Daily feed intake was not different between CTR and PS cows across the pre- and postpartum periods. However, due to constraints in animal housing management, individual feed intake measures were limited to 35 d BEC to 15 DIM, when animals were in tiestalls. Treatments that increase milk production find that milk yield increase often precedes changes in feed intake (
      • Peters R.R.
      • Chapin L.T.
      • Leining K.B.
      • Tucker H.A.
      Supplemental lighting stimulates growth and lactation in cattle.
      ;
      • Sechen S.J.
      • McCutcheon S.N.
      • Bauman D.E.
      Response to metabolic challenges in early lactation dairy cows during treatment with bovine somatotropin.
      ;
      • McDowell G.H.
      Somatotropin and endocrine regulation of metabolism during lactation.
      ). However, in the longer term, treatment-induced higher milk production needs to be supported by greater feed intake of dairy cattle. Therefore, we expect that the greater milk production to 60 DIM of PS versus CTR cows was supported by greater feed intake when animals entered the freestall barn.

      CONCLUSIONS

      We hypothesized that disruption of the circadian timing system during the preparturition period would affect nutrient metabolism and reduce milk production. Findings confirmed that the chronic light–dark phase shift treatment affected the central clock outputs, resting behavior, glucose metabolism, and milk production; however, results were contrary to our hypothesis. Analysis of body temperature and melatonin revealed attenuation of these circadian rhythms in PS cows. Further studies need to be performed to elucidate the effect of chronic light–dark phase shifts on tissue-specific clocks and metabolism, although our findings suggest that attenuation of rhythms likely results in a more constant milieu of hormones and metabolites.

      ACKNOWLEDGMENTS

      This work is supported by the Agriculture and Food Research Initiative (AFRI) competitive grant no. 2017-67015-26569 project accession no. 1011965 from the USDA National Institute of Food and Agriculture (Washington, DC). The authors gratefully acknowledge the technical assistance of the Animal Sciences Research and Education Center (Purdue University, West Lafayette, IN) staff, Holly Kyler-Sibray, Gary Wernert, Chad Myers, and Gregory Milam. The authors have not stated any conflicts of interest.

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