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No description available.

The circadian system uses environmental cues to coordinate the plethora of physiological functions that occur with diurnal rhythmicity, with light being one of the strongest regulators of the circadian system. The suprachiasmatic nucleus (SCN) is positioned at the top of the circadian hierarchy, receiving photic input from the retina and using neuronal, humoral and endocrine signals to synchronize oscillatory patterns across virtually all organ systems. Though the circadian system is plastic to deviations from a normal light/dark (LD) cycle, there are biological limits as to the rate and degree to which the SCN can adapt to these deviations, with peripheral oscillators responding in a delayed manner to the master clock. Alzheimer’s disease (AD) has long been linked to disruptions in the circadian system, with circadian deficits generally portrayed as a consequence of disease development. Recent evidence, however, suggests that circadian disruptions may precede noticeable cognitive deficits associated with AD. Our study aims to determine whether inducible circadian disruption via exposure to our social jetlag protocol, taking advantage of manipulating light exposure to disrupt the circadian system, can exacerbate the rate and severity of AD pathology in both the AβPP/PS1 and APPNL-F/NL-F mouse models of AD. AβPP/PS1 and APPNL-F/NL-F subjected to a preliminary study at 2-4 months in which overall activity in normal LD conditions, re-entrainment to a maintained 8-hour phase advance of the LD cycle, and endogenous period in constant darkness were measured. Glucose Tolerance Test (GTT) was used to assess metabolic health. Following the preliminary study, wild type (WT; C57BL/6J) controls, AβPP/PS1 and APPNL-F/NL-F AD models were entrained to a control light/dark cycle starting at 6 weeks of age. Following 2-weeks of entrainment, half of the animals were maintained on the control schedule, and half were exposed to the social jetlag protocol, involving an 8-hour phase advance on day 5 and an 8-hour phase delay on day 7 of repeated 7-day sessions, effectively inducing chronic circadian disruption until the assigned 6 and 12-month endpoints. One month prior to the endpoint, activity measures and GTT were performed, following which the animals were all entrained to a normal 12:12 LD schedule for 3-5 weeks. Finally, animals underwent an 8-day Morris Water Maze (MWM) to assess effects of chronic disruption on AD-related cognitive decline. Animals were then sacrificed and tissues collected at Zeitgeber time (ZT) 12, time of lights off. At 2-4 months of age, preclinical stages in both AD models, APPNL-F/NL-F males displayed significantly higher fasting glucose levels and circadian period (day length). There were trending increases in overall activity levels under normal 12:12 LD conditions in both AD models over WT controls. 2-4 month females re-entrained to an 8-hour phase advance in significantly less time than males in all genotypes. AβPP/PS1 mice demonstrated hyperactivity as compared to age and sex-matched WT controls. Chronic circadian disruption dampened lights off activity in all cohorts. In all genotypes, female animals showed a higher degree of re-entrainment to the phase advancement of the lighting schedule going into the subjective weekend (day 6-7). Metabolic data as measured by glucose tolerance test on day 7 of the (social jet lag) SJL schedule indicated that disrupted animals were metabolically entrained to the day 1-5 schedule at the peak of rhythmic metabolic function, whereas control animals were at a low point in metabolic rhythms at the time of testing, indicating that circadian regulation of metabolic function was not able to adapt to the weekend phase shifts. Arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) expression in the SCN were significantly dampened as a result of chronic disruption in 12-month male AD mice. Amyloid plaque analysis indicated a severely worsened pathological phenotype in AβPP/PS1 mice as compared to age and sex-matched APPNL-F/NL-F mice. MWM data provides evidence for impaired spatial learning in both AD models that is significantly worsened by chronic jetlag exposure. Taken together, the data suggests that chronic exposure to the social jet lag schedule disrupts rhythmic behavior, metabolic function, and spatial learning significantly in both AD animal models.

Alcohol use disorder (AUD) is the leading cause of substance use disorders among Veterans and 55 to 75% of the population that are diagnosed with PTSD also receive a comorbid diagnosis of AUD. The co-diagnosis of PTSD/AUD is associated with neurocognitive changes such as increased impulsivity and risk-taking behavior, especially among individuals with combat-related trauma. Furthermore, increased neuroinflammation in subregions of the prefrontal cortex (PFC) are suggested to contribute to these neurocognitive changes. To better understand the cognitive deficits associated with co-occurring PTSD/AUD we incorporated a probabilistic discounting task (PDT) to model risk-based decision-making in male and female Wistar rats that were exposed to restraint stress (RS) and chronic intermittent ethanol exposure (CIE). Following RS and CIE, rats underwent lever press training through a series of different training phases, in which one lever delivered a small reward 100% of the time, and the other a large reward, delivered with descending probability each trial block. Pressing the large-reward lever during the final two trial blocks when it is disadvantageous to do so is considered “risky” behavior. A week prior to PDT, rats were treated prophylactically with CDPPB, a positive allosteric modulator of the metabotropic glutamate type 5 (mGlu5) receptor, to determine if the cognitive deficits caused by stress and alcohol exposure could be prevented. Additionally, to determine if our model mimicked the neuroinflammatory mechanism seen in the human condition and the therapeutic effects of CDPPB, we assessed TNF-⍺ protein expression in a subset of rats. Our results indicated that male rats exposed to RS and CIE had significantly greater responding during the 3rd, 4th, and 5th risk blocks compared to all other groups. However, the administration of CDPPB reversed this effect. Females exposed to RS and CIE only displayed increased risky behavior at the highest risk block and this was also blocked with the administration of CDPPB. We also determined that RS and CIE significantly increased TNF-⍺ levels in the IfL cortex compared to either RS or CIE alone and the prophylactic administration of CDPPB reduced TNF-⍺ protein expression to control animal levels. In the present study, we demonstrate that exposure to stress and chronic alcohol leads to significant neurocognitive deficits resulting in increased risky decision-making, but these deficits can be attenuated through modulation of the mGlu5 receptor prior to behavioral testing. Additionally, these deficits could be due to deleterious neuroinflammation in subregions of the PFC.

No description available.

No description available.

No description available.

Studies have demonstrated dissociable effects of nicotine alone versus in combination with ethanol on learning, and these effects may depend on different neural substrates. Furthermore, the effects of nicotine in different brain areas may produce other behavioral changes - such as changes in anxiety - that alter learning. This research examines the interactive effects of ethanol and nicotine on learning, anxiety, and locomotion, and the dissociation of these effects by brain area. Specifically, we examine the interactive effects of systemic ethanol with nicotine infusion into the dorsal hippocampus, ventral hippocampus, or anterior cingulate on contextual and cued fear conditioning and the plus-maze discriminative avoidance task (PMDAT). In addition, we use dihydro-beta-erythroidine (DHbetaE), a nicotinic receptor antagonist, to examine the involvement of acetylcholingeric nicotinic receptors (nAChRs) in the effects of ethanol alone and in the mediation of ethanol-induced changes by nicotine. In the PMDAT, we examine whether caffeine produces the same effects as nicotine in the PMDAT. In fear conditioning, nicotine acts in the dorsal hippocampus to enhance contextual fear conditioning and in the anterior cingulate to reverse ethanol-induced contextual and cued fear conditioning deficits through inactivation of high-affinity beta2 subunit-containing nAChRs. In the PMDAT, ethanol produces learning deficits, anxiolysis, and increased locomotion, and nicotine reverses the effects of ethanol. Although caffeine and ethanol interact to modulate behavior in the PMDAT, caffeine fails to reverse ethanol-induced learning deficits. Finally, the effects of nicotine and ethanol, both alone and in combination, on learning, anxiety, and locomotion depend on distinct neural substrates. Nicotine acts in the anterior cingulate to reverse ethanol-induced learning deficits but produces diverse effects on anxiety that vary across all three brain areas. / Psychology

Animals perform a myriad of behaviors such as object tracking and spatial navigation, primarily in the absence of explicit target signals. In the absence of targets, neural circuits must implement a different target function. One primary theory for self-supervised learning is predictive learning, in which a system predicts feedforward signals over time, and in which internal representations emerge to provide longer-term structural information. While such theories are inspired by neural properties, they often lack direct links to low-level neural mechanisms. In the first study, a model of the formation of internal representations is presented. I introduce the canonical microcircuit of cortical structures, including general connectivity and unique physiological properties of neural subpopulations. I then introduce a learning rule based on the contrast of feedforward potentials in pyramidal neurons with their feedback-controlled burst rates. Utilizing these two signals the learning rule instantiates a feedback-gated temporal error minimization. Combined with a set of feedforward-only units and organized hierarchically, the model learns to tracks the dynamics of external stimuli with high accuracy, and successive regions are shown to code temporal derivatives of their feedforward inputs. The second study presents an electrophysiological experiment which showed a novel functional cell type in the retrosplenial cortex of behaving Long-Evans rats. Through rigorous statistical analysis we show that these neurons contain a egocentric representation of boundary locations. Combined with their location in the cortical hierarchy, this suggests that the retrosplenial neurons provide a mechanism for translating self-centered sensory information to the map-like representations present in subcortical structures. In the final study I integrate the basic modular architecture of the first study with the specific afferent stimuli and macroscale connectivity patterns involved in spatial navigation. I simulate an agent in a simple virtual environment and compare the learned representations to tuning curves from experiments such as study two. I find the expected development of neural responses corresponding to egocentric sensory representations (retrosplenial cortex), self-oriented allocentric coding (postrhinal cortex) and allocentric spatial representations (hippocampus). Together, these modeling results show how self-gated and guided learning in pyramidal ensembles can form useful and stable internal representations depending on the task at hand.

Hypothermia therapy (HT) is used clinically following global cerebral ischemia (GCI) but its therapeutic mechanisms are not completely understood. An elucidation of such mechanisms may lead to novel therapeutic approaches that improve patient outcome. Using a murine model of GCI, we determined the effect of HT on the expression of inflammatory proteins in the hippocampus and serum. We also examined its effect on microglia/macrophage activation and neurodegeneration in the brain at 72 hours following ischemia, and its effect on long-term spatial memory/learning and contextual fear response. GCI led to increased neurodegeneration and microglia/macrophage activation in the hippocampus, and increased IL-1β and KC protein expression in the hippocampus at 72 hours. Hypothermia therapy attenuated these inflammatory responses. It also improved spatial learning/memory at 7 and 21 days, and preserved contextual fear response 21 days post-ischemia. Hypothermia therapy attenuated the post-ischemic inflammatory response, protected hippocampal neurons, and preserved long-term memory and learning.