Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:

Cholinergic-Sensitive Theta Oscillations in Memory Encoding in Mice.

Cholinergic regulation of hippocampal theta oscillations has long been proposed to be a potential mechanism underlying hippocampus-dependent memory encoding processes. However, cholinergic transmission has been traditionally associated with type II theta under urethane anesthesia. The mechanisms and behavioral significance of cholinergic regulation of type I theta in freely exploring animals is much less clear. In this study, we examined the potential behavioral significance of cholinergic regulation of theta oscillations in the object location task in male mice that involves training and testing trials and provides an ideal behavioral task to study the underlying memory encoding and retrieval processes, respectively. Cholinergic regulation of hippocampal theta oscillations and the behavioral outcomes was examined by either intrahippocampal infusion of cholinergic receptor antagonists or knocking out cholinergic receptors in excitatory neurons or interneurons. We found that both muscarinic acetylcholine receptors (mAChRs) and α7 nicotinic AChRs (α7 nAChRs) regulated memory encoding by engaging excitatory neurons and interneurons, respectively. There is a transient upregulated theta oscillation at the beginning of individual object exploration events that only occurred in the training trials, but not in the testing trials. This transient upregulated theta is also the only theta component that significantly differed between training and testing trials and was sensitive to mAChR and α7 nAChR antagonists. Thus, our study has revealed a transient cholinergic-sensitive theta component that is specifically associated with memory encoding, but not memory retrieval, in the object location task, providing direct experimental evidence supporting a role for cholinergic-regulated theta oscillations in hippocampus-dependent memory encoding processes.

Assessing the importance of sex in a hippocampus-dependent behavioral test battery in C57BL/6NTac mice.

Inclusion of male and female subjects in behavioral neuroscience research requires a concerted effort to characterize sex differences in standardized behavioral assays. Sex differences in hippocampus-dependent assays have been widely reported but are still poorly characterized. In the present study, we conducted a parametric analysis of spontaneous alternation, object recognition, and fear conditioning in a commonly used control strain, C57BL/6NTac. Our findings show largely similar performance between males and females across the majority of behavioral end points. However, we identified an important difference in nonassociative fear sensitization, whereby females showed an enhanced fear response to the 75-dB tone that is used as the conditional stimulus. In addition, we observed an impairment in object location performance in females that was ameliorated by more extensive habituation to handling. Together, these findings argue that sex differences in nonassociative fear responses to both novel auditory cues and novel objects need to be considered when designing and interpreting cognitive assays in C57BL/6 mice. Furthermore, this elevated fear sensitization could serve as a novel approach to model the increased incidence of anxiety disorders in women.

Differential signalling induced by α7 nicotinic acetylcholine receptors in hippocampal dentate gyrus in vitro and in vivo.

The activation of α7 nicotinic acetylcholine receptors (nAChRs) has been shown to improve hippocampus-dependent learning and memory. α7 nAChRs are densely expressed among several different cell types in the hippocampus, with high Ca2+  permeability, although it is unclear if α7 nAChRs mobilize differential signalling mechanisms among distinct neuronal populations. To address this question, we compared α7 nAChR agonist-induced responses (i.e. calcium and cAMP changes) between granule cells and GABAergic neurons in the hippocampal dentate gyrus both in vitro and in vivo. In cultured organotypic hippocampal slices, we observed robust intracellular calcium and cAMP increases in dentate granule cells upon activation of α7 nAChRs. In contrast, GABAergic interneurons displayed little change in either calcium or cAMP concentration after α7 nAChR activation, even though they displayed much larger α7 nAChR current responses than those of dentate granule cells. We found that this was due to smaller α7 nAChR-induced Ca2+ rises in GABAergic interneurons. Thus, the regulation of the Ca2+ transients in different cell types resulted in differential subsequent intracellular signalling cascades and likely the ultimate outcome of α7 nAChR activation. Furthermore, we monitored neuronal activities of dentate granule cells and GABAergic interneurons in vivo via optic fibre photometry. We observed enhancement of neuronal activities after nicotine administration in dentate granule cells, but not in GABAergic neurons, which was absent in α7 nAChR-deficient granule cells. In summary, we reveal a mechanism for α7 nAChR-mediated increase of neuronal activity via cell type-specific intracellular signalling pathways. KEY POINTS: α7 nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system and regulate a variety of brain functions including learning and memory. Understanding the cellular signalling mechanisms of their activations among different neuronal populations is important for delineating their actions in cognitive function, and developing effective treatment strategies for cognitive deficits. We report that α7 nAChR activation leads to Ca2+ and cAMP increases in granule cells (but not in GABAergic interneurons) in hippocampal dentate gyrus in vitro, a key region for pattern separation during learning. We also found that nicotine enhanced granule cell (but not in GABAergic interneurons) activity in an α7 nAChR-dependent manner via in vivo fibre photometry recording. Based on our findings, we propose that differential responses to α7 nAChR activation between granule cells and GABAergic interneurons is responsible for the increase of excitation by α7 nAChR agonists in hippocampal circuits synergistically.

Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC), a gastrointestinal inflammatory disease of unknown etiology that may also affect the liver, causes a great deal of morbidity and mortality in premature infants. We tested the hypothesis that signaling molecules, which are endogenous to the bowel, regulate the severity of intestinal and hepatic damage in an established murine NEC model. Specifically, we postulated that mucosal serotonin (5-HT), which is proinflammatory, would exacerbate experimental NEC and that oxytocin (OT), which is present in enteric neurons and is anti-inflammatory, would oppose it. Genetic deletion of the 5-HT transporter (SERT), which increases and prolongs effects of 5-HT, was found to increase the severity of systemic manifestations, intestinal inflammation, and associated hepatotoxicity of experimental NEC. In contrast, genetic deletion of tryptophan hydroxylase 1 (TPH1), which is responsible for 5-HT biosynthesis in enterochromaffin (EC) cells of the intestinal mucosa, and TPH inhibition with LP-920540 both decrease the severity of experimental NEC in the small intestine and liver. These observations suggest that 5-HT from EC cells helps to drive the inflammatory damage to the gut and liver that occurs in the murine NEC model. Administration of OT decreased, while the OT receptor antagonist atosiban exacerbated, the intestinal inflammation of experimental NEC. Data from the current investigation are consistent with the tested hypotheses-that the enteric signaling molecules, 5-HT (positively) and OT (negatively) regulate severity of inflammation in a mouse model of NEC. Moreover, we suggest that mucosally restricted inhibition of 5-HT biosynthesis and/or administration of OT may be useful in the treatment of NEC.NEW & NOTEWORTHY Serotonin (5-HT) and oxytocin reciprocally regulate the severity of intestinal inflammation and hepatotoxicity in a murine model of necrotizing enterocolitis (NEC). Selective depletion of mucosal 5-HT through genetic deletion or inhibition of tryptophan hydroxylase-1 ameliorates, while deletion of the 5-HT uptake transporter, which increases 5-HT availability, exacerbates the severity of NEC. In contrast, oxytocin reduces, while the oxytocin receptor antagonist atosiban enhances, NEC severity. Peripheral tryptophan hydroxylase inhibition may be useful in treatment of NEC.

Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine.

OBJECTIVE: Enterochromaffin cell-derived serotonin (5-HT) promotes intestinal inflammation. We tested hypotheses that peripheral tryptophan hydroxylase (TPH) inhibitors, administered orally, block 5-HT biosynthesis and deplete 5-HT from enterochromaffin cells sufficiently to ameliorate intestinal inflammation; moreover, peripheral TPH inhibitors fail to enter the murine enteric nervous system (ENS) or central nervous systems and thus do not affect constitutive gastrointestinal motility. DESIGN: Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate (LX1032; LX1606) were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Quantitation of clinical scores, histological damage and intestinal expression of inflammation-associated cytokines and chemokines with focused microarrays and real-time reverse transcriptase PCR were employed to evaluate the severity of intestinal inflammation. RESULTS: LP-920540 and LX1032 reduced 5-HT significantly in the gut and blood but not in the brain. Neither LP-920540 nor LX1032 decreased 5-HT immunoreactive neurons or fibres in the myenteric plexus and neither altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. In contrast, oral LP-920540 and LX1032 reduced the severity of TNBS-induced colitis; the expression of 24% of 84 genes encoding inflammation-related cytokines and chemokines was lowered at least fourfold and the reduced expression of 17% was statistically significant. CONCLUSIONS: Observations suggest that that peripheral TPH inhibitors uncouple the positive linkage of enterochromaffin cell-derived 5-HT to intestinal inflammation. Because peripheral TPH inhibitors evidently do not enter the murine ENS, they lack deleterious effects on constitutive intestinal motility in mice.

FiPhA: an open-source platform for fiber photometry analysis.

Significance: Fiber photometry (FP) is a widely used technique in modern behavioral neuroscience, employing genetically encoded fluorescent sensors to monitor neural activity and neurotransmitter release in awake-behaving animals. However, analyzing photometry data can be both laborious and time-consuming. Aim: We propose the fiber photometry analysis (FiPhA) app, which is a general-purpose FP analysis application. The goal is to develop a pipeline suitable for a wide range of photometry approaches, including spectrally resolved, camera-based, and lock-in demodulation. Approach: FiPhA was developed using the R Shiny framework and offers interactive visualization, quality control, and batch processing functionalities in a user-friendly interface. Results: This application simplifies and streamlines the analysis process, thereby reducing labor and time requirements. It offers interactive visualizations, event-triggered average processing, powerful tools for filtering behavioral events, and quality control features. Conclusions: FiPhA is a valuable tool for behavioral neuroscientists working with discrete, event-based FP data. It addresses the challenges associated with analyzing and investigating such data, offering a robust and user-friendly solution without the complexity of having to hand-design custom analysis pipelines. This application thus helps standardize an approach to FP analysis.

Sex differences in spontaneous behavior and cognition in mice using an automated behavior monitoring system.

Isolation of sex differences as a key characteristic underlying neurobehavioral differentiation is an essential component of studies in neuroscience. The current study sought to address this concern by observing behavioral differences using an automated home cage system for neurobehavioral assessment, a method rapidly increasing in use due to advances in technology and advantages such as reduced handling stress and cross-lab variability. Sex differences in C57BL/6 mice arose for motor activity and circadian-linked behavior, with females being more active compared to males, and males having a stronger anticipatory increase in activity leading up to the onset of the light phase compared to females. These activity differences were observed not only across the lifespan, but also in different genetic background mouse strains across different testing sites showing the generalizability and robustness of these observed effects. Activity differences were also observed in performance on a spatial learning and reversal task with females making more responses and receiving a corresponding elevation in reward pellets. Notably, there were no sex differences in learning nor achieved accuracy, suggesting these observed effects were predominantly in activity. The outcomes of this study align with previous reports showcasing differences in activity between males and females. The comparison across strains and testing sites showed robust and reproducible differences in behavior between female and male mice that are relevant to consider when designing behavioral studies. Furthermore, the observed sex differences in performance on the learning and reversal procedure raise concern for interpretation of behavior differences between sexes due to the attribution of these differences to motor activity rather than cognition.

FiPhA: An Open-Source Platform for Fiber Photometry Analysis.

Significance: Fiber photometry is a widely used technique in modern behavioral neuroscience, employing genetically encoded fluorescent sensors to monitor neural activity and neurotransmitter release in awake-behaving animals, However, analyzing photometry data can be both laborious and time-consuming. Aim: We propose the FiPhA (Fiber Photometry Analysis) app, which is a general-purpose fiber photometry analysis application. The goal is to develop a pipeline suitable for a wide range of photometry approaches, including spectrally resolved, camera-based, and lock-in demodulation. Approach: FiPhA was developed using the R Shiny framework and offers interactive visualization, quality control, and batch processing functionalities in a user-friendly interface. Results: This application simplifies and streamlines the analysis process, thereby reducing labor and time requirements. It offers interactive visualizations, event-triggered average processing, powerful tools for filtering behavioral events and quality control features. Conclusions: FiPhA is a valuable tool for behavioral neuroscientists working with discrete, event-based fiber photometry data. It addresses the challenges associated with analyzing and investigating such data, offering a robust and user-friendly solution without the complexity of having to hand-design custom analysis pipelines. This application thus helps standardize an approach to fiber photometry analysis.

Genetic deletion of α7 nAChRs reduces hippocampal granule and pyramidal cell number in both sexes but impairs pattern separation in males only.

Introduction: Neurogenesis within the dentate gyrus is thought to play an important role in cognitive processes such as reversal learning and pattern separation. The α7 nicotinic acetylcholine receptor (α7 nAChR) is expressed early in newly formed granule cells of the dentate gyrus, though its role in neurogenesis and related cognitive function is not fully understood. Methods: To better characterize relevant function of α7 nAChRs, we performed unbiased stereology to quantify hippocampal granule cells, pyramidal cells, and total volume and used a touchscreen operant spatial discrimination/reversal task to test pattern separation in a global α7 nAChR knockout mouse line. Results: The knockout resulted in an ≈22% reduction in granule cells and a ≈ 20% reduction in pyramidal cells in both sexes, with no change in total hippocampal volume. However, the knockout impaired performance in the touchscreen task for males only. The sex-dependent difference in behavioral, but not stereological, results suggest a divergence in the structure-function relationship in males versus females. Detailed analyses revealed males were more biased by the initial reversal contingency relative to females indicating a potential source of the sex-specific interaction with the loss of α7 nAChRs. Discussion: These findings argue that the α7 nAChR plays a critical role in hippocampal development, not just granule cell neurogenesis, and plays a sex-dependent role in cognitive function.

Enteric neuronal density contributes to the severity of intestinal inflammation.

BACKGROUND & AIMS: Enteric neurons have been reported to be increased in inflamed regions of the bowel in patients with inflammatory bowel disease or intestinal neurogangliomatosis. It is impossible to determine whether this hyperinnervation predates intestinal inflammation, results from it, or contributes to its severity in humans, so we studied this process in mice. METHODS: To determine whether the density of enteric neurons determines the severity of inflammation, we studied transgenic mice that have greater than normal (NSE-noggin mice, which overexpress noggin under the control of the neuron-specific enolase promoter) or fewer than normal (Hand2(+/-) mice) numbers of neurons in the enteric nervous system. Colitis was induced with trinitrobenzene sulfonic acid or dextran sulfate sodium, and the intensity of the resulting inflammation in Hand2(+/-) and NSE-noggin mice was compared with that of wild-type littermates. RESULTS: Severity of each form of colitis (based on survival, symptom, and histologic scores; intestinal expression of genes that encode proinflammatory molecules; and levels of neutrophil elastase and p50 nuclear factor κB) were significantly reduced in Hand2(+/-) mice and significantly increased in NSE-noggin animals. Neither mouse differed from wild-type in the severity of delayed-type hypersensitivity (edema, T-cell and neutrophil infiltration, or expression of interleukin-1ß, interferon-γ, or tumor necrosis factor-α) induced in the ears using 2,4-dinitro-1-fluorobenzene. Transgene effects on inflammation were therefore restricted to the gastrointestinal tract. CONCLUSIONS: The severity of intestinal inflammation is associated with the density of the enteric innervation in mice. Abnormalities in development of the enteric nervous system might therefore contribute to the pathogenesis of inflammatory bowel disease.

Expression level of Hand2 affects specification of enteric neurons and gastrointestinal function in mice.

BACKGROUND & AIMS: Hand2 is a basic helix-loop-helix transcription factor required for terminal differentiation of enteric neurons. We studied Hand2 haploinsufficient mice, to determine whether reduced expression of Hand2 allows sufficient enteric neurogenesis for survival, but not for development of a normal enteric nervous system (ENS). METHODS: Enteric transcripts that encode Hand2 and the neuron-specific embryonic lethal abnormal vision proteins HuB, HuC, and HuD were quantified. Immunocytochemistry was used to identify and quantify neurons. Apoptosis was analyzed with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling procedure. Intracellular microelectrodes were used to record inhibitory junction potentials. Gastrointestinal transit and colonic motility were measured in vivo. RESULTS: Levels of of enteric Hand2 transcripts were associated with genotypes of mice, in the following order: Hand2(+/+) > Hand2(LoxP/+) > Hand2(+/-) > Hand2(LoxP/-). Parallel reductions were found in expression of HuD and in regional and phenotypic manners. Numbers of neurons, numbers of neuronal nitric oxide synthase(+) and calretinin(+), but not substance P(+) or vasoactive intestinal peptide(+) neurons, decreased. No effects were observed in stomach or cecum. Apoptosis was not detected, consistent with the concept that Hand2 inhibits neuronal differentiation, rather than regulates survival. The amplitude of inhibitory junction potentials in colonic circular muscle was similar in Hand2 wild-type and haploinsufficient mice, although in haploinsufficient mice, the purinergic component was reduced and a nitrergic component appeared. The abnormal ENS of haploinsufficient mice slowed gastrointestinal motility but protected mice against colitis. CONCLUSIONS: Reduced expression of factors required for development of the ENS can cause defects in the ENS that are subtle enough to escape detection yet cause significant abnormalities in bowel function.

3D-Printed Capacitive Sensor Objects for Object Recognition Assays.

Object recognition tasks are widely used assays for studying learning and memory in rodents. Object recognition typically involves familiarizing mice with a set of objects and then presenting a novel object or displacing an object to a novel location or context. Learning and memory are inferred by a relative increase in time investigating the novel/displaced object. These tasks are in widespread use, but there are many inconsistencies in the way they are conducted across labs. Two major contributors to this are the lack of consistency in the method of measuring object investigation and the lack of standardization of the objects that are used. Current video-based automated algorithms can often be unreliable whereas manual scoring of object investigation is time consuming, tedious, and more subjective. To resolve these issues, we sought to design and implement 3D-printed objects that can be standardized across labs and use capacitive sensing to measure object investigation. Using a 3D printer, conductive filament, and low-cost off-the-shelf components, we demonstrate that employing 3D-printed capacitive touch objects is a reliable and precise way to perform object recognition tasks. Ultimately, this approach will lead to increased standardization and consistency across labs, which will greatly improve basic and translational research into learning and memory mechanisms.

Loss of α7 nicotinic acetylcholine receptors in GABAergic neurons causes sex-dependent decreases in radial glia-like cell quantity and impairments in cognitive and social behavior.

The dentate gyrus (DG) is a unique brain structure in that neurons can be generated postnatally and integrated within existing circuitry throughout life. The maturation process of these newly generated neurons (granule cells) is modulated by nicotinic acetylcholine receptors (nAChRs) through a variety of mechanisms such as neural stem pool proliferation, cell survival, signal modulation, and dendritic integration. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, predominantly the α7 subtype, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined histological and behavioral effects of knocking out α7 nAChRs in GABAergic neurons. Deletion of α7 nAChRs resulted in a reduction of radial glia-like cells within the subgranular zone of the DG and a concomitant trend towards decreased immature neurons, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition and spatial learning. Overall, these findings suggest α7 nAChRs expressed in GABAergic neurons play an important role in regulating the adult neural stem cell pool and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.

Inhibition of casein kinase 1 δ/ε improves cognitive performance in adult C57BL/6J mice.

Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1δ/ε, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1δ/ε inhibition in improving time-of-day cognitive performance.

A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice.

PGC1α is a transcriptional coactivator in peripheral tissues, but its function in the brain remains poorly understood. Various brain-specific Pgc1α isoforms have been reported in mice and humans, including two fusion transcripts (FTs) with non-coding repetitive sequences, but their function is unknown. The FTs initiate at a simple sequence repeat locus ∼570 Kb upstream from the reference promoter; one also includes a portion of a short interspersed nuclear element (SINE). Using publicly available genomics data, here we show that the SINE FT is the predominant form of Pgc1α in neurons. Furthermore, mutation of the SINE in mice leads to altered behavioural phenotypes and significant up-regulation of genes in the female, but not male, cerebellum. Surprisingly, these genes are largely involved in neurotransmission, having poor association with the classical mitochondrial or antioxidant programs. These data expand our knowledge on the role of Pgc1α in neuronal physiology and suggest that different isoforms may have distinct functions. They also highlight the need for further studies before modulating levels of Pgc1α in the brain for therapeutic purposes.

Alcohol Intake Increases in Adolescent C57BL/6J Mice during Intermittent Cycles of Phase-Delayed, Long-Light Conditions.

Adolescents naturally go to bed and awaken late, but are forced to awaken early for school and work. This leads to "social jetlag", a state of circadian desynchrony (CD), in which internal biological rhythms are out of sync with behavioral rhythms. CD is associated with increased alcohol intake in adults, but has been less well-studied in adolescents. The goal of this study was to model adolescent alcohol intake during similar CD conditions in male C57BL/6J mice. Free access alcohol intake, water intake and wheel-running activity were measured during a normal 12HR photoperiod or during alternating photoperiod (Experiment 1: 12 h light for 4 days followed by 18 h light for 3 days, with dark (activity onset) delayed 9 h during the 18HR photoperiod; Experiment 2: 12 h light for 4 days followed by 6 h light for 3 days, with dark onset delayed 3 h during the 6HR photoperiod). In Experiment 1, CD produced a small but significant increase in the total alcohol intake per day as well as in intake in bouts, with the greatest increase over controls in the hours following the 6HR dark period. Additionally, the pattern of alcohol intake in bouts shifted to increase alcohol intake during the shorter dark period. In Experiment 2, the opposite effect occurred-the longer dark cycle led to lower alcohol drinking in the second half of the dark period. However, in Experiment 2, CD produced no significant changes in either total alcohol intake or alcohol intake in bouts. CONCLUSION: shifts in the light cycle that disrupt the regular pattern of day and night, and increase the length of the night phase, are sufficient to increase both drinking in bouts and restricted drinking in adolescent mice, modeling increased alcohol intake in adolescents during CD.

Disruption of normal circadian clock function in a mouse model of tauopathy.

Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to ß-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.