Biology subjects

Epp, J. R.

Publications and source records attributed to Epp, J. R..

15 recordsLinked to original sources

bioRxiv2025

Inhibitory Circuit Compensations in Female and Male Mice: Increased Synaptic Output Offsets Reduced Parvalbumin Interneuron Density

Parvalbumin inhibitory interneurons (PV-INs) are critical regulators of excitatory/inhibitory balance in the cortex, and their dysfunction has been observed in various neurological disorders. Despite increasing recognition of sex differences in brain function, little is known about how PV-INs differ between males and females under healthy conditions. Previous work has pointed to sex differences in PV-IN vulnerability in disease and injury models. Here, we investigated sex differences in PV-IN characteristics, connectivity, and function in the retrosplenial cortex (RSC) of healthy mice. We found that female mice have significantly fewer PV-INs in the RSC compared to males, yet exhibit comparable memory induced neuronal activation (fos expression). Despite their lower numbers, female PV-INs displayed greater synaptic connectivity, as evidenced by increased synaptotagmin-2 (Syt-2) puncta per PV-IN and higher axonal bouton density. Additionally, fewer female PV-INs were surrounded by perineuronal nets (PNNs), suggesting greater plasticity in female inhibitory networks. From ex vivo slice electrophysiology recordings we observed greater excitability in female PV-INs compared to male PV-INs and, a reduced incidence of IPSCs. These findings indicate that female mice may compensate for reduced PV-IN numbers through enhanced synaptic output, preserving inhibitory function in the RSC. Finally, using spatial transcriptomic profiling of PV-INs we observed a number of differentially expressed genes that are consistent with the observed structural and functional differences between female and male PV-INs. Understanding these sex-specific inhibitory mechanisms is crucial for developing more targeted interventions for conditions involving PV-IN impairment and for understanding sex specific vulnerabilities to certain conditions such as Alzheimers disease.

neuroscience↗

bioRxiv2025

Parity and APOEε4 genotype contribute distinct changes to functional connectivity across the middle-aged brain

Cognition and its underlying neurobiology change throughout the trajectory of aging, with prominent sex differences and influences of sex-specific factors. Research has shown that parity (pregnancy and parenthood) uniquely altered various biomarkers of brain health in middle age depending on presence of Alzheimers disease (AD) risk. The present study builds on prior work by providing a comprehensive view of functional connectivity changes and elucidating how network-level dynamics contribute to cognitive outcomes depending on primiparity and APOE{varepsilon}4 genotype, the top genetic risk factor for late-onset sporadic AD risk. We assessed neural activation in middle-aged wildtype and hAPOE{varepsilon}4 rats that were either nulliparous (0 litters) or primiparous (1 litter). Activation of the immediate early gene zif268 was quantified across 19 brain regions implicated in memory and AD. Primiparous hAPOE{varepsilon}4 rats exhibited widespread reductions in neural activation, particularly in the dorsal striatum, nucleus accumbens, frontal cortex, and retrosplenial cortex. Network analyses further revealed that primiparous wildtype rats had the most cohesive and efficient functional connectivity networks. Notably, the hierarchy of influence of brain regions within the neural network shifted based on parity and hAPOE{varepsilon}4 genotype. Activation of hippocampal new-born neurons in conjunction with subregions of the dorsal striatum, frontal cortex, and retrosplenial cortex dynamically predicted cognitive performance in a parity- and genotype-dependent manner. These findings underscore the lasting impact of reproductive history on brain health and cognitive aging, highlighting the need to consider sex-specific experiences in aging and AD research.

neuroscience↗

bioRxiv2025

Cognitive enrichment preserves retrosplenial parvalbumin density and cognitive function in female 5xFAD mice

BACKGROUNDThe rate of cognitive decline in Alzheimers disease (AD) varies considerably from person to person. Numerous epidemiological studies point to the protective effects of cognitive, social, and physical enrichment as potential mediators of cognitive decline in AD; however, there is much debate as to the mechanism underlying these effects. The retrosplenial cortex (RSC) is one of the earliest brain regions with impaired functions during AD pathogenesis, and its activity is affected by cognitive, social, and physical stimulation. METHODSIn the current study, we use the 5xFAD mouse mode of AD to examine the impact of enriched housing conditions on cognitive function in AD and the viability of a particularly vulnerable cell population within the RSC - parvalbumin interneurons (PV-INs). RESULTSEnriched housing conditions improved cognitive performance in 5xFAD mice. These changes in cognitive performance coincided with restored functional connectivity of the RSC and preserved PV-IN density within this region. Along with preserved PV-IN density, there was an increase in the density of perineuronal nets (PNNs) across the RSC of 5xFAD mice housed in enriched conditions. Direct manipulation of PNNs revealed that these extracellular matrix structures protect PV-INs from amyloid toxicity. CONCLUSIONSTogether, these results provide support for the PNN-mediated maintenance of PV-INs in the RSC as a potential mechanism mediating the protective effects of enrichment against cognitive decline in AD.

neuroscience↗

bioRxiv2023

Neurogenesis-mediated circuit remodeling reduces engram reinstatement and promotes forgetting

Post-training increases in hippocampal neurogenesis are associated with forgetting of hippocampus-dependent memories in adult mice. This form of forgetting might be due to increased numbers of new neurons, remodeling of hippocampal circuitry or some combination of both. Here we tested the hypothesis that neurogenesis-mediated forgetting is caused by remodeling of hippocampal circuits by engineering mice in which adult-generated granule cells hypo- or hyper-integrate into hippocampal circuits. Using gene deletion, opto- and chemogenetic strategies, we find that hypo-integration of newborn neurons prevents post- training exercise-induced forgetting of contextual fear memories. Conversely, inducing hyper- integration of newborn neurons following contextual fear conditioning is sufficient to produce forgetting. Because these interventions did not affect survival of newborn neurons, these findings suggest that neurogenesis-mediated remodeling of hippocampal circuits represents a continuous and active form of interference that alters accessibility of engrams underlying hippocampal memories. Consistent with this, using engram-labeling approaches, we found that exercise-induced forgetting was associated with reduced engram reactivation.

neuroscience↗

bioRxiv2023

Long-term impact of early life stress on serotonin connectivity

Chronic childhood stress is a prominent risk factor for developing mood disorders, yet mechanisms underlying this association remain unclear. Serotonin (5-HT) plays a crucial role in neurodevelopment and vulnerability to mood disorders. Maintenance of optimal 5-HT levels during early postnatal development is critical for the maturation of brain circuits. Developmental stress can alter the serotonin system, leading to chronic behavioral deficits. Yet, our understanding of the long-term impact of early life stress (ELS) on serotonin connectivity remains incomplete. Using a mouse model of chronic developmental stress, we sought to determine how ELS impacts brain-wide serotonin activity and behavior in adulthood. We established that adult female and male mice exposed to ELS during the first postnatal week show heightened anxiety-like behavior. Using in vivo fiber photometry and c-fos dependent activity mapping, we found that ELS enhances susceptibility to acute stress by disrupting the brain-wide functional connectivity of the raphe nucleus and the activity of dorsal raphe serotonin neuron population, in conjunction with a profound increase in the orbitofrontal cortex (OFC) activity. We further identified that 5-HT release in the medial OFC during environmental challenge is disrupted in mice exposed to ELS. Optogenetic stimulation of 5-HT terminals in the mOFC elicited an anxiolytic effect in ELS mice in a sex-dependent manner. Our findings hold significant insight into the mechanisms underlying long-term brain connectivity deficits induced by ELS, with potential implications for developing targeted stimulation-based treatments for affective disorders that arise from early life adversities.

neuroscience↗

bioRxiv2023

Sex-dependent impairments of parvalbumin expressing neurons in the retrosplenial cortex in Alzheimer's disease

Alzheimers disease is a debilitating neurodegenerative disorder with no cure and few treatment options. In early stages of Alzheimers disease, impaired metabolism, and functional connectivity of the retrosplenial cortex strongly predict future cognitive impairments. Therefore, understanding Alzheimers disease-related deficits in the retrosplenial cortex is critical for understanding the origins of cognitive impairment and identifying early treatment targets. Using the 5xFAD mouse model, we discovered early, sex-dependent alterations in parvalbumin-interneuron transcriptomic profiles. This corresponded with impaired parvalbumin-interneuron activity, which was sufficient to induce cognitive impairments and dysregulate retrosplenial functional connectivity. In fMRI scans from patients with mild cognitive impairment and Alzheimers disease, we observed a similar sex-dependent dysregulation of retrosplenial cortex functional connectivity and, in post-mortem tissue from subjects with Alzheimers disease, a loss of parvalbumin interneurons. Reversal of cognitive deficits by stimulation of parvalbumin interneurons in the retrosplenial cortex suggests that this may serve as a promising novel therapeutic strategy. One Sentence SummaryAltered function, connectivity, and survival of parvalbumin expressing neurons in the retrosplenial cortex in Alzheimers Disease.

neuroscience↗

bioRxiv2023

Classifying high-dimensional phenotypes with ensemble learning

O_LIClassification is a fundamental task in biology used to assign members to a class. While linear discriminant functions have long been effective, advances in phenotypic data collection are yielding increasingly high-dimensional datasets with more classes, unequal class covariances, and non-linear distributions. Numerous studies have deployed machine learning techniques to classify such distributions, but they are often restricted to a particular organism, a limited set of algorithms, and/or a specific classification task. In addition, the utility of ensemble learning or the strategic combination of models has not been fully explored. C_LIO_LIWe performed a meta-analysis of 33 algorithms across 20 datasets containing over 20,000 high-dimensional shape phenotypes using an ensemble learning framework. Both binary (e.g., sex, environment) and multi-class (e.g., species, genotype, population) classification tasks were considered. The ensemble workflow contains functions for preprocessing, training individual learners and ensembles, and model evaluation. We evaluated algorithm performance within and among datasets. Furthermore, we quantified the extent to which various dataset and phenotypic properties impact performance. C_LIO_LIWe found that discriminant analysis variants and neural networks were the most accurate base learners on average. However, their performance varied substantially between datasets. Ensemble models achieved the highest performance on average, both within and among datasets, increasing average accuracy by up to 3% over the top base learner. Higher class R2 values, mean class shape distances, and between- vs. within-class variances were positively associated with performance, whereas higher class covariance distances were negatively associated. Class balance and total sample size were not predictive. C_LIO_LILearning-based classification is a complex task driven by many hyperparameters. We demonstrate that selecting and optimizing an algorithm based on the results of another study is a flawed strategy. Ensemble models instead offer a flexible approach that is data agnostic and exceptionally accurate. By assessing the impact of various dataset and phenotypic properties on classification performance, we also offer potential explanations for variation in performance. Researchers interested in maximizing performance stand to benefit from the simplicity and effectiveness of our approach made accessible via the R package pheble. C_LI

bioinformatics↗

bioRxiv2022

Sex-dependent role of hypocretin/orexin neurons in social behavior

Intraspecies social interactions are integral for survival and maintenance of society among all mammalian species. Yet, our understanding of the neural systems and mechanisms involved in the establishment of social connectedness are limited. Since their initial discovery as regulators of sleep/wakefulness and appetite in the brain, the hypocretin/orexin neurons have also been shown to play an essential role in modulating energy homeostasis, motivated and emotional behavior. These neurons are located exclusively in the hypothalamus which, regulates complex and goal-directed behaviors. The hypothalamus also plays an important role in the modulation of social behavior by encoding internal states. However, our understanding of the role of hypocretin neurons in social behavior is currently limited. To address this knowledge gap, we performed a combination of fiber photometry and machine learning based behavioral analysis in female and male mice expressing GCaMP6s in hypocretin neurons. We then applied optogenetic and pharmacological inhibition of hypocretin neuron signaling to determine the necessity of the hcrt neuron population for social behavior. Our results indicate that hypocretin neurons exhibit a robust increase in activity in response to social interaction in both female and male mice. We show here for the first time a social discrimination signal that is encoded differentially by hcrt neurons based on the nature of the social encounter. The intensity of the hcrt neuron activity predicts the subsequent duration of social interaction. The optogenetic inhibition of hypocretin neuron activity during social behavior leads to a reduction in the amount of time mice are engaged in social interaction in males but not in females. Blocking hcrt1 (orexin 1) receptors similarly reduces social interaction in males only. Reduced hcrt1 receptor signaling results in increased activity in the insular cortex and reduced activity in the VTA after social interaction in male mice. Together, these data implicate the lateral hypothalamus hypocretin neurons as a sexually dimorphic key regulator within the larger network of neural systems involved in social behavior. Our findings carry significant implications for the treatment of neuropsychiatric diseases characterized by social dysfunction, particularly considering the varying prevalence observed across different sexes.

neuroscience↗

bioRxiv2022

Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated activity

BackgroundRepetitive transcranial magnetic stimulation (rTMS) induces action potentials to induce plastic changes in the brain with increasing evidence for the therapeutic importance of brain-wide functional network effects of rTMS; however, the influence of sub-action potential threshold (low-intensity; LI-) rTMS on neuronal activity is largely unknown. HypothesisWe investigated whether LI-rTMS modulates neuronal activity and functional connectivity. We also specifically assessed modulation of parvalbumin interneuron activity. MethodsWe conducted a brain-wide analysis of c-Fos, a marker for neuronal activity, in mice that received LI-rTMS to visual cortex. Mice received single or multiple sessions of excitatory 10Hz LI-rTMS with custom rodent coils or were sham controls. We assessed changes to c-Fos positive cell densities and c-Fos/parvalbumin co-expression. Peak c-Fos expression corresponded with activity during rTMS. We also assessed functional connectivity changes using brain-wide c-Fos-based network analysis. ResultsLI-rTMS modulated c-Fos expression in cortical and subcortical regions. c-Fos density changes were most prevalent with acute stimulation, however chronic stimulation decreased parvalbumin interneuron activity, most prominently in the amygdala and striatum. LI-rTMS also increased anti-correlated functional connectivity, with the most prominent effects also in the amygdala and striatum following chronic stimulation. ConclusionLI-rTMS induces changes in c-Fos expression that suggest modulation of neuronal activity and functional connectivity throughout the brain. Our results suggest that LI-rTMS promotes anticorrelated functional connectivity, possibly due to decreased parvalbumin interneuron activation induced by chronic stimulation. These changes may underpin therapeutic rTMS effects, therefore modulation of subcortical activity supports rTMS for treatment of disorders involving subcortical dysregulation. Highlights- Low-intensity rTMS increases brain-wide anti-correlated functional connectivity - Acute excitatory LI-rTMS modulates cortical and subcortical neuronal activity - Decreased parvalbumin interneuron activity may promote anti-correlated activity - Striatum and amygdala show prominent modulation with LI-rTMS

neuroscience↗

bioRxiv2021

New neurons in old brains: A cautionary tale for the analysis of neurogenesis in post-mortem tissue.

Adult neurogenesis has primarily been examined in two key regions in the mammalian brain, the subgranular zone of the hippocampus and the subventricular zone. The proliferation and integration of newly generated neurons has been observed widely in adult mammalian species including the human hippocampus. Recent high-profile studies have suggested however, that this process is considerably reduced in humans, occurring in children but declining rapidly and nearly completely in the adult brain. In comparison, rodent studies also show age-related decline but a greater degree of proliferation of new neurons in adult animals. Here, we examine whether differences in tissue fixation, rather than biological difference in human versus rodent studies might account for the diminished levels of neurogenesis sometimes observed in the human brain. To do so we analyzed neurogenesis in the hippocampus of rats that were either perfusion-fixed or the brains extracted and immersion-fixed at various post-mortem intervals. We observed an interaction between animal age and the time delay between death and tissue fixation. While similar levels of neurogenesis were observed in young rats regardless of fixation, older rats had significantly fewer labeled neurons when fixation was not immediate. Furthermore, the morphological detail of the labeled neurons was significantly reduced in the delayed fixation conditions at all ages. This study highlights critical concerns that must be considered when using post-mortem tissue to quantify adult neurogenesis.

neuroscience↗

bioRxiv2021

Toxoplasma infection alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Toxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During chronic infection, T. gondii can migrate to the brain where it promotes low-grade neuroinflammation with the capacity to induce changes in brain morphology and behavior. Consequently, infection with T. gondii has been linked with a number of neurocognitive disorders including schizophrenia (SZ), dementia, and Parkinsons disease. Beyond neuroinflammation, infection with T. gondii can modulate the production of neurotransmitters, such as dopamine. To further dissect these pathways and examine the impact of altered dopaminergic sensitivity in T. gondii-infected mice on both behavior and gene expression, we developed a novel mouse model, based on stimulant-induced (cocaine) hyperactivity. Employing this model, we found that infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviurs. While both behaviors may help reduce predator avoidance, consistent with previous studies, the latter finding is reminiscent of neurocognitive disorders. Applying RNASeq to two relevant brain regions, striatum and hippocampus, we identified a broad upregulation of immune responses. However, we also noted significant associations with more meaningful neurologically relevant terms were masked due to the sheer number of terms incorporated in multiple testing correction. We therefore performed a more focused analysis using a curated set of neurologically relevant terms revealing significant associations across multiple pathways. We also found that T. gondii and cocaine treatments impacted the expression of similar functional pathways in the hippocampus and striatum although, as indicated by the low overlap among differentially expressed genes, largely via different proteins. Furthermore, while most differentially expressed genes reacted to a single condition and were mostly upregulated, we identified gene expression patterns indicating unexpected interactions between T. gondii infection and cocaine exposure. These include sets of genes which responded to cocaine exposure but not upon cocaine exposure in the context of T. gondii infection, suggestive of a neuroprotective effect advantageous to parasite persistence. Given its ability to uncover such complex relationships, we propose this novel model offers a new perspective to dissect the molecular pathways by which T. gondii infection contributes to neuropsychiatric disorders such as schizophrenia.

microbiology↗

bioRxiv2021

Brain-wide neuronal activation and functional connectivity are modulated by prior exposure to repetitive learning episodes.

Memory storage and retrieval are shaped by past experiences. Prior learning and memory episodes have numerous impacts on brain structure from micro to macroscale. Previous experience with specific forms of learning increases the efficiency of future learning. It is less clear whether such practice effects on one type of memory might also have transferable effects to other forms of memory. Different forms of learning and memory rely on different brain-wide networks but there are many points of overlap in these networks. Enhanced structural or functional connectivity caused by one type of learning may be transferable to another type of learning due to overlap in underlying memory networks. Here, we investigated the impact of prior chronic spatial training on the task-specific functional connectivity related to subsequent contextual fear memory recall in mice. Our results show that mice exposed to prior spatial training exhibited decreased brain-wide activation compared to control mice during the retrieval of a context fear memory. With respect to functional connectivity, we observed changes in several network measures notably an increase in global efficiency. Interestingly, we also observed an increase in network resilience based on simulated targeted node deletion. Overall, this study suggests that chronic learning has transferable effects on the functional connectivity networks of other types of learning and memory. The generalized enhancements in network efficiency and resilience suggest that learning itself may protect brain networks against deterioration.

neuroscience↗

bioRxiv2021

Neurogenesis-mediated forgetting of complex paired-associates memories

The hippocampus is a critical structure involved in many forms of learning and memory. It is also one of the only regions in the adult mammalian brain that continues to generate new neurons throughout adulthood. This process of adult neurogenesis may increase the plasticity of the hippocampus which could be beneficial for learning but has also been demonstrated to decrease the stability of previously acquired memories. Here we test whether increased production of new neurons following the formation of a gradually acquired paired-associates task will result in forgetting of this type of memory. We trained mice in a touchscreen-based object/location task and then increased neurogenesis using voluntary exercise. Our results indicate that mice with increased neurogenesis show poor recall of the previously established memory. When subsequently exposed to a reversal task we also show that mice with increased neurogenesis require fewer correction trials to acquire the new task contingencies. This suggests that prior forgetting reduces perseveration on the now outdated memory. Together our results add to a growing body of literature which indicates the important role of adult neurogenesis in destabilizing previously acquired memories to allow for flexible encoding of new memories.

animal behavior and cognition↗

bioRxiv2021

Neurogenesis-induced forgetting is associated with reduced neuronal activity in CA1 during context fear memory retrieval

Adult hippocampal neurogenesis has been demonstrated to affect learning and memory in numerous ways. Several studies have now demonstrated that increased neurogenesis can induce forgetting of memories acquired prior to the manipulation of neurogenesis and, as a result of this forgetting can also facilitate new learning. However, the mechanisms mediating neurogenesis-induced forgetting are not well understood. Here, we used a subregion-based analysis of the immediate early gene c-Fos as well as in vivo fiber photometry to determine changes in activity corresponding with neurogenesis induced forgetting. We found that increasing neurogenesis led to reduced CA1 activity during context memory retrieval. We also demonstrate here that perineuronal net expression in areas CA1 is bidirectionally altered by the levels or activity of adult generated neurons in the dentate gyrus. These results suggest that neurogenesis may induce forgetting by disrupting perineuronal nets in CA1 which may otherwise protect memories from degradation.

neuroscience↗

bioRxiv2021

Adult neurogenesis mediates forgetting of multiple types of memory in the rat

The formation and retention of hippocampus-dependent memories is impacted by neurogenesis, a process that involves the production of new neurons in the dentate gyrus of the hippocampus. Recent studies demonstrate that increasing neurogenesis after memory formation induces forgetting of previously acquired memories. Neurogenesis-induced forgetting was originally demonstrated in mice, but a recent report suggests that the same effect may be absent in rats. Although a general species difference is possible, other potential explanations for these incongruent findings are that memories which are more strongly reinforced become resilient to forgetting or that perhaps only certain types of memories are affected. Here, we investigated whether neurogenesis-induced forgetting occurs in rats using several hippocampal dependent tasks including contextual fear conditioning (CFC), the Morris Water Task (MWT), and touchscreen paired associates learning (PAL). Neurogenesis was increased following training using voluntary exercise for 4 weeks before recall of the previous memory was assessed. We show that voluntary running causes forgetting of context fear memories in a neurogenesis-dependent manner, and that neurogenesis-induced forgetting is present in rats across behavioral tasks despite differences in complexity or reliance on spatial, context, or object memories. In addition, we asked whether stronger memories are less susceptible to forgetting by varying the strength of training. Even with a very strong training protocol in the CFC task, we still observed enhanced forgetting related to increased neurogenesis. These results suggest that forgetting due to neurogenesis is a conserved mechanism that aids in the clearance of memories. Significance StatementRecent evidence indicates that hippocampal neurogenesis mediates forgetting of older memories and enhances encoding of new memories free of proactive interference. This evidence comes from multiple rodent species, behavioral tasks, and methods of increasing neurogenesis. However, a recent paper by (Kodali et al. 2016) found that voluntary exercise-induced neurogenesis did not cause forgetting in the Morris Water Task in rats. The results call into question whether the phenomenon is a conserved function of neurogenesis across species. In the present study, we show that voluntary running causes robust forgetting in rats in a neurogenesis-dependent manner and that the effect is present across three different behavioral tasks, confirming the existence of the phenomenon in rats and adding to the growing evidence that forgetting is a conserved function of hippocampal neurogenesis.

neuroscience↗