About

Dr. David J. Earnest is a professor in the Department of Neuroscience and Experimental Therapeutics at Texas A&M University. His research focuses on the cellular and molecular neurobiology of mammalian circadian rhythms, emphasizing the regulation of 24-hour or circadian rhythms by the master biological clock in the suprachiasmatic nucleus (SCN) and peripheral clocks throughout the body. His work investigates how normal circadian regulation impacts human health and how disruptions in these rhythms are linked to disorders such as obesity, diabetes, cancer, cardiovascular disease, sleep disturbances, and depression. Dr. Earnest employs multidisciplinary approaches to study the cellular mechanisms of circadian clocks and the signal transduction pathways responsible for circadian photoentrainment. His current projects include exploring the roles of microRNAs and signaling molecules in local circadian clocks, the interactions between circadian mechanisms, inflammatory signaling, and metabolism, and the mechanisms linking circadian disruption with metabolic disorders and neuroprotective responses. He participates in graduate training as a member of the Interdisciplinary Program in Neuroscience and is an executive member of the TAMU Center for Biological Clocks Research.

Research topics

• Internal medicine
• Medicine
• Psychology
• Developmental psychology
• Audiology
• Cardiology
• Physiology
• Intensive care medicine
• Neuroscience

Selected publications

• Shift work schedules alter immune cell regulation and accelerate cognitive impairment during aging

  Journal of Neuroinflammation · 2025-01-08 · 6 citations

  articleOpen accessSenior author

  BACKGROUND: Disturbances of the sleep-wake cycle and other circadian rhythms typically precede the age-related deficits in learning and memory, suggesting that these alterations in circadian timekeeping may contribute to the progressive cognitive decline during aging. The present study examined the role of immune cell activation and inflammation in the link between circadian rhythm dysregulation and cognitive impairment in aging. METHODS: C57Bl/6J mice were exposed to shifted light-dark (LD) cycles (12 h advance/5d) during early adulthood (from ≈ 4-6mo) or continuously to a "fixed" LD12:12 schedule. At middle age (13-14mo), the long-term effects of circadian rhythm dysregulation on cognitive performance, immune cell regulation and hippocampal microglia were analyzed using behavioral, flow cytometry and immunohistochemical assays. RESULTS: Entrainment of the activity rhythm was stable in all mice on a fixed LD 12:12 cycle but was fully compromised during exposure to shifted LD cycles. Even during "post-treatment" exposure to standard LD 12:12 conditions, re-entrainment in shifted LD mice was marked by altered patterns of entrainment and increased day-to-day variability in activity onset times that persisted into middle-age. These alterations in light-dark entrainment were closely associated with dramatic impairment in the Barnes maze test for the entire group of shifted LD mice at middle age, well before cognitive decline was first observed in aged (18-22mo) animals maintained on fixed LD cycles. In conjunction with the effects of circadian dysregulation on cognition, shifted LD mice at middle age were distinguished by significant expansion of splenic B cells and B cell subtypes expressing the activation marker CD69 or inflammatory marker MHC Class II Invariant peptide (CLIP), differential increases in CLIP+, 41BB-Ligand+, and CD74 + B cells in the meningeal lymphatics, alterations in splenic T cell subtypes, and increased number and altered functional state of microglia in the dentate gyrus. In shifted LD mice, the expansion in splenic B cells was negatively correlated with cognitive performance; when B cell numbers were higher, performance was worse in the Barnes maze. These results indicate that disordered circadian timekeeping associated with early exposure to shift work-like schedules alone accelerates cognitive decline during aging in conjunction with altered regulation of immune cells and microglia in the brain.

  PublisherOA PDFDOI

• Shift Work Schedules Alter Immune Cell Regulation and Accelerate Cognitive Impairment during Aging

  Research Square · 2024-12-04

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• The impact of burnout and self-compassion on graduate students in mental health settings

  PsycEXTRA Dataset · 2023-01-01

  datasetSenior author
  PublisherDOI

• Sex differences in the diathetic effects of shift work schedules on circulating cytokine levels and pathological outcomes of ischemic stroke during middle age

  Neurobiology of Sleep and Circadian Rhythms · 2022-06-23 · 8 citations

  articleOpen access1st authorCorresponding

  Shift work is associated with increased risk for vascular disease, including stroke- and cardiovascular-related mortality. However, evidence from these studies is inadequate to distinguish the effect of altered circadian rhythms in isolation from other risk factors for stroke associated with shift work (e.g., smoking, poor diet, lower socioeconomic status). Thus, the present study examined the diathetic effects of exposure to shifted LD cycles during early adulthood on circadian rhythmicity, inflammatory signaling and ischemic stroke pathology during middle age, when stroke risk is high and outcomes are more severe. Entrainment of circadian activity was stable in all animals maintained on a fixed light:dark 12:12 cycle but was severely disrupted during exposure to shifted LD cycles (12hr advance/5d). Following treatment, circadian entrainment in the shifted LD group was distinguished by increased daytime activity and decreased rhythm amplitude that persisted into middle-age. Circadian rhythm desynchronization in shifted LD males and females was accompanied by significant elevations in circulating levels of the inflammatory cytokine IL-17A and gut-derived inflammatory mediator lipopolysaccharide (LPS) during the post-treatment period. Middle-cerebral artery occlusion, 3 months after exposure to shifted LD cycles, resulted in greater post-stroke mortality in shifted LD females. In surviving subjects, sensorimotor performance, assessed 2- and 5-days post-stroke, was impaired in males of both treatment groups, whereas in females, recovery of function was observed in fixed but not shifted LD rats. Overall, these results indicate that early exposure to shifted LD cycles promotes an inflammatory phenotype that amplifies stroke impairments, specifically in females, later in life.

  PublisherDOI

• Development of an age-dependent cognitive index: relationship between impaired learning and disturbances in circadian timekeeping

  Frontiers in Aging Neuroscience · 2022 · 16 citations

  Senior authorCorresponding
  • Psychology
  • Audiology
  • Neuroscience

  Preclinical quantitative models of cognitive performance are necessary for translation from basic research to clinical studies. In rodents, non-cognitive factors are a potential influence on testing outcome and high variability in behavior requires multiple time point testing for better assessment of performance in more sophisticated tests. Thus, these models have limited translational value as most human cognitive tests characterize cognition using single digit scales to distinguish between impaired and unimpaired function. To address these limitations, we developed a cognitive index for learning based on previously described scores for strategies used by mice to escape the Barnes maze. We compared the cognitive index and circadian patterns of light-dark entrainment in young (4-6 months), middle-aged (13-14 months), and aged (18-24 months) mice as cognitive changes during aging are often accompanied by pronounced changes in sleep-wake cycle. Following continuous analysis of circadian wheel-running activity (30-40 days), the same cohorts of mice were tested in the Barnes maze. Aged mice showed significant deficits in the learning and memory portions of the Barnes maze relative to young and middle-aged animals, and the cognitive index was positively correlated to the memory portion of the task (probe) in all groups. Significant age-related alterations in circadian entrainment of the activity rhythm were observed in the middle-aged and aged cohorts. In middle-aged mice, the delayed phase angle of entrainment and increased variability in the daily onsets of activity preceded learning and memory deficits observed in aged animals. Interestingly, learning-impaired mice were distinguished by a positive relationship between the extent of Barnes-related cognitive impairment and variability in daily onsets of circadian activity. While it is unclear whether changes in the sleep-wake cycle or other circadian rhythms play a role in cognitive impairment during aging, our results suggest that circadian rhythm perturbations or misalignment may nevertheless provide an early predictor of age-related cognitive decline.

  PublisherOA PDFDOI

• Cognitive changes and circadian timekeeping disturbances in aging

  Alzheimer s & Dementia · 2022-12-01

  articleSenior author

  Abstract Background Cognitive changes in aging and Alzheimer’s disease (AD) are often accompanied by pronounced disturbances of circadian timekeeping, especially sleep‐wake cycle. Normal circadian timekeeping has an important impact on human health and performance by providing the temporal coordination of internal processes to insure their occurrence at the “right time” relative to each other and to the external environment. Aging of the rodent circadian system is characterized by changes comparable to those in human aging and AD. Common disturbances in the sleep‐wake rhythms of aged rodents include alterations in the light‐dark entrainment of this circadian rhythm. However, not all aged rodents show these changes, demonstrating the variability characteristic of human aging in pre‐dementia. The aging population also shows variability in onset and magnitude of cognitive impairment, but the relationship between these deficits with circadian rhythm disturbances has not yet been identified. Method Initially, we tested young (3‐5 mon) and aged (18‐24 mon) C57Bl6 mice on wheel running activity continuously for 30‐40 days for circadian rhythm of locomotor activity. We then assessed learning and memory in the same mice using the Barnes maze task. Next, we wanted to determine if behavioral deficits occurred earlier in the lifespan (middle age) and whether changes in circadian activity occur prior to cognitive impairment. Result Aged mice were significantly impaired in all measures of activity rhythm entrainment and cognition. Interestingly, we observed a gender‐specific relationship between cognitive impairment in the Barnes maze and activity onset in aged female mice (20‐24 mon). Changes in activity rhythm entrainment were observed as early as 12‐14 months in middle aged mice. We also tested these mice for cognition (Barnes maze, novel and spatial recognition tests, 3 chamber sociability test) and motor behavior (rotarod, open field and digigait). Conclusion This data will be the foundation of our model to further understand the relationship between circadian synchronization and age‐related cognitive impairment, and to probe possible mechanisms of action.

  PublisherDOI

• Toward Precision Medicine: Circadian Rhythm of Blood Pressure and Chronotherapy for Hypertension - 2021 NHLBI Workshop Report

  Hypertension · 2022 · 87 citations

  • Medicine
  • Intensive care medicine
  • Internal medicine

  Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

  PublisherOA PDFDOI

• Amitriptyline Decreases GABAergic Transmission in Basal Forebrain Neurons Using an Optogenetic Model of Aging

  Frontiers in Aging Neuroscience · 2021-05-28 · 12 citations

  articleOpen access

  The antidepressant drug amitriptyline is used in the treatment of clinical depression and a variety of neurological conditions such as anxiety, neuropathic pain disorders and migraine. Antidepressants are associated with both therapeutic and untoward effects, and their use in the elderly has tripled since the mid-1990s. Because of this widespread use, we are interested in testing the acute effects of amitriptyline on synaptic transmission at therapeutic concentrations well below those that block voltage-gated calcium channels. We found that 3 μM amitriptyline reduced the frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and reduced quantal content in mice at ages of 7-10 mo. and 23-25 mo., suggesting a presynaptic mechanism of action that does not diminish with age. We employed a reduced synaptic preparation of the basal forebrain (BF) and a new optogenetic aging model utilizing a bacterial artificial chromosome (BAC) transgenic mouse line with stable expression of the channelrhodopsin-2 (ChR2) variant H134R specific for GABAergic neurons [VGAT-ChR2(H134R)-EYFP]. This model enables optogenetic light stimulation of specific GABAergic synaptic terminals across aging. Age-related impairment of circadian behavior was used to confirm predictable age-related changes associated with this model. Our results suggest that low concentrations of amitriptyline act presynaptically to reduce neurotransmitter release and that this action is maintained during aging.

  PublisherOA PDFDOI

• Role of Proinflammatory Cytokines in Feedback Modulation of Circadian Clock Gene Rhythms by Saturated Fatty Acids

  Scientific Reports · 2019-06-20 · 18 citations

  articleOpen accessSenior author

  Proinflammatory signaling cascades have been implicated in the mechanism by which high fat diet (HFD) and saturated fatty acids (SFA) modulate fundamental circadian properties of peripheral clocks. Because the cytokines TNFα and IL-6 are key signals in HFD- and SFA-induced proinflammatory responses that ultimately lead to systemic insulin resistance, the present study examined the roles of these cytokines in the feedback modulation of peripheral circadian clocks by the proinflammatory SFA, palmitate. IL-6 and TNFα secretion in Bmal1-dLuc fibroblast cultures was increased during palmitate treatment although the time course and amplitude of the inductive response differed between these cytokines. Similar to the time-dependent phase shifts observed in response to palmitate, treatment with IL-6 or with the low dose (0.1 ng/ml) of TNFα at hour 12 (i.e., after forskolin synchronization) induced phase advances of fibroblast Bmal1-dLuc rhythms. In complementary experiments, treatment with neutralizing antibodies against these proinflammatory cytokines or their receptors to inhibit of IL-6- or TNFα-mediated signaling repressed palmitate-induced phase shifts of the fibroblast clock. These studies suggest that TNFα, IL-6 and other proinflammatory cytokines may mediate the feedback modulation of peripheral circadian clocks by SFA-induced inflammatory signaling.

  PublisherOA PDFDOI

• PWE-076 Efficacy of Pharmacological Therapies in Patients with Irritable Bowel Syndrome with Diarrhoea: Network Meta-analysis

  2019-06-01

  articleOpen access

  <h3>Introduction</h3> Over half of patients with irritable bowel syndrome have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licensed pharmacological therapies in IBS-D and IBS-M is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. <h3>Methods</h3> We searched MEDLINE, EMBASE, EMBASE Classic, the Cochrane central register of controlled trials, and clinicaltrials.gov through November 2018 to identify randomised controlled trials (RCTs) assessing the efficacy of licensed pharmacological therapies in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk of remaining symptomatic with 95% confidence intervals (CIs) to summarise the effect of each comparison tested. Treatments were ranked according to their P-score. <h3>Results</h3> We identified 18 eligible RCTs (7 alosetron, 5 ramosetron, 2 rifaximin, 4 eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS (Figure 1). Alosetron 1mg twice-daily ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency (RR = 0.69; 95% CI 0.60 to 0.80, P-score = 0.97), effect on global symptoms of IBS, and effect on stool consistency. Ramosetron 2.5mcg once-daily was ranked first for effect on abdominal pain (RR = 0.75; 95% CI 0.65 to 0.85, P-score = 0.94). Total numbers of adverse events were significantly greater with alosetron 1mg twice-daily and ramosetron 2.5mcg, once-daily, compared with placebo. Rifaximin 550mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550mg three times daily. <h3>Conclusions</h3> In a network meta-analysis of randomised controlled trials of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.

  PublisherOA PDFDOI

Recent grants

• NIH Grant P01NS039546

  NIH · $16.3M · 2012

• NIH Grant R01MH060147

  NIH · $568k · 2005

• NIH Grant F32MH009129

  NIH · $45k

• NIH Grant R55NS030939

  NIH · $100k · 1994

• NIH Grant R29NS024661

  NIH · $493k · 1992

Frequent coauthors

• Gregg C. Allen

  Texas A&M University

  44 shared

• Nichole Neuendorff

  Texas A&M Health Science Center

  37 shared

• Yuhua Z. Farnell

  Texas A&M University

  20 shared

• Vincent M. Cassone

  University of Kentucky

  18 shared

• David S. Alberts

  University of Arizona

  16 shared

• James R. West

  13 shared

• Manju Batta

  Veterans Biomedical Research Institute

  12 shared

• Fong-Qi Liang

  Retina Foundation of the Southwest

  12 shared

Labs

• Department of Neuroscience & Experimental TherapeuticsPI

Education

• PhD, Neurobiology

  Northwestern University

  1984

• MS, Neurobiology

  Northwestern University

  1979

• BS, Zoology

  University of Michigan

  1976