Biology subjects

Jasnow, A. M.

Publications and source records attributed to Jasnow, A. M..

6 recordsLinked to original sources

bioRxiv2025

Restoring DSCAM expression rescues neuronal morphology and axon guidance deficits in Down syndrome

Down syndrome (DS) results from the triplication of human chromosome 21 (HSA21) and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on HSA21 and is overproduced in DS. DSCAM is a receptor for netrin-1 and important for neural wiring in the developing brain. Using a Dscam gain-of-function mouse model and human induced pluripotent stem cell (hiPSC)-derived cortical neurons, in combination with cellular, molecular, and behavioral approaches, this study aims to understand how DSCAM triplication and its subsequent excessive production contribute to changes in neural development and intellectual disability in DS. Analysis of morphological parameters revealed impaired neuronal development and loss of netrin-1-mediated axon guidance in mouse hippocampal pyramidal neurons overexpressing DSCAM. Furthermore, DSCAM overexpression reduces interhemispheric connectivity in vivo, and hippocampal- dependent learning in adult mice. DS hiPSC-derived excitatory pyramidal neurons exhibit a similar phenotype: impaired morphological development and loss of netrin-1-mediated axon guidance. Remarkably, normalization of DSCAM in DS hiPSC-derived neurons rescues many of these neuronal phenotypes, including reduced axon length and deficits in axon guidance. These results suggest that DSCAM plays an essential role in the development of neurons and neuronal networks, and its overproduction contributes to intellectual disability in DS.

neuroscience↗

bioRxiv2025

An amygdala-cortical circuit for encoding generalized fear memories.

Generalized learning is a fundamental process observed across species, contexts, and sensory modalities that enables animals to use past experiences to adapt to changing conditions. Evidence suggests that the prefrontal cortex (PFC) extracts general features of an experience that can be used across multiple situations. The anterior cingulate cortex (ACC), a region of the PFC, is implicated in generalized fear responses to novel contexts. However, the ACCs role in encoding contextual information is poorly understood, especially under increased threat intensity that promotes generalization. Here, we show that synaptic plasticity within the ACC and signaling from amygdala inputs during fear learning are necessary for generalized fear responses to novel encountered contexts. The ACC did not encode specific fear to the training context, suggesting this region extracts general features of a threatening experience rather than specific contextual information. Together with our previous work, our results demonstrate that generalized learning about threatening contexts is encoded, in part, within an ascending amygdala-cortical circuit, whereas descending ACC projections to the amygdala drive generalized fear responses during exposure to novel contexts. Our results further demonstrate that schematic learning can occur in the PFC after single-trial learning, a process typically attributed to learning over many repeated learning episodes.

neuroscience↗

bioRxiv2024

Male and female mice respectively form stronger social aversive memories with same and different sex conspecifics

Mice offer a wealth of opportunities for investigating brain circuits regulating multiple behaviors, largely due to their genetic tractability. Social behaviors are translationally relevant, considering both mice and humans are highly social mammals, and human social behavior disruptions are key symptoms of myriad neuropsychiatric disorders. Stresses related to social experiences are particularly influential in the severity and maintenance of neuropsychiatric disorders like anxiety disorders, and trauma and stressor-related disorders. Yet, induction and study of social stress in mice has disproportionately focused on males, influenced heavily by their inherent territorial nature. Social target-instigated stress (i.e., defeat), while ethologically relevant, is quite variable and predominantly specific to males, making rigorous and sex-inclusive studies challenging. In pursuit of a controllable, consistent, high throughput, and sex-inclusive method for social stress elicitation, we modified a paradigm to train male and female F1 129S1/SvlmJ x C57BL/6J mice to associate (via classical conditioning) same or different sex C57BL/6J targets with a mild, aversive stimulus. While further paradigm optimization is required, social interaction testing 24 h after conditioning indicates males socially conditioned better to male targets by exhibiting reduced social interaction, whereas females appeared not to form social stimulus associations. Serum corticosterone levels inversely corresponded to social avoidance after different sex, but not same sex, conditioning, suggesting corticosterone-mediated arousal influences cross-sex interactions. These rigorously controlled null outcomes align with past pursuits limited success in creating a sex-inclusive social stress paradigm. Significance StatementValidated paradigms to study social stress in female mice, and across sexes, are needed. We modified a published male mouse protocol by using classical conditioning to pair an aversive stressor with a target. Our goal was to create a uniform, cross-sex, high-throughput social stress technique to advance future research. Though our modified paradigm requires future improvements, we did acquire evidence that males can be socially conditioned in this way, and female same sex social engagement can be attenuated by a preceding non-social aversive experience. These null findings, while not achieving our goal, provide useful information to advance future sex-inclusive social stress investigations.

neuroscience↗

bioRxiv2024

The role of locus coeruleus neuroimmune signaling in the response to social stress in female rats

Neuropsychiatric disorders that result from stress exposure are highly associated with central inflammation. Our previous work established that females selectively exhibit heightened proinflammatory cytokine production within the noradrenergic locus coeruleus (LC) along with a hypervigilant behavioral phenotype in response to witnessing social stress, and ablation of microglia using pharmacological techniques prevents this behavioral response. These studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using chemogenetics. We first characterized the use of an AAV-CD68-Gi-DREADD virus targeted to microglia within the LC and confirmed viral transduction, selectivity, and efficacy. Clozapine-n-oxide (CNO) was used for the suppression of microglial reactivity during acute and chronic exposure to vicarious/witness social defeat in female rats. Chemogenetic-mediated inhibition of microglial reactivity during stress blunted the neuroimmune response to stress and prevented both acute and long-term hypervigilant behavioral responses. Further, a history of microglial suppression during stress prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit microglia within the female brain in vivo and establish LC inflammation as a key mechanism underlying the behavioral and neuronal responses to social stress in females.

neuroscience↗

bioRxiv2023

Sex divergent behavioral responses in platform-mediated avoidance and glucocorticoid receptor blockade

Women are more likely than men to develop anxiety or stress-related disorders. A core behavioral symptom of all anxiety disorders is avoidance of fear or anxiety eliciting cues. Recent rodent models of avoidance show reliable reproduction of this behavioral phenomenon in response to learned aversive associations. Here, a modified version of platform-mediated avoidance that lacked an appetitive task was utilized to investigate the learning and extinction of avoidance in male and female C57BL6/J mice. Here, we found a robust sex difference in the acquisition and extinction of platform-mediated avoidance. Across three experiments, 63.7% of female mice acquired avoidance according to our criterion, whereas 83.8% of males acquired it successfully. Of those females that acquired avoidance, they displayed persistent avoidance after extinction compared to males. Given their role in regulating stress responses and habitual behaviors, we investigated if glucocorticoid receptors (GR) mediated avoidance learning in males and females. Here we found that a subcutaneous injection (25mg/kg) of the GR antagonist, RU486 (mifepristone), significantly reduced persistent avoidance in females but did not further reduce avoidance in males after extinction. These data suggest that GR activation during avoidance learning may contribute to persistent avoidance in females that is resistant to extinction.

neuroscience↗

bioRxiv2019

Anterior cingulate cortex and ventral hippocampal inputs to the basolateral amygdala selectively control generalized fear

Nearly one third of Americans have been afflicted with an anxiety disorder. A common symptom of anxiety disorders is the over generalization of fear across a broad range of contextual cues. We previously found that the anterior cingulate cortex and ventral hippocampus (vHPC) regulate generalized fear. Here, we investigate the functional projections from the ACC and vHPC to the amygdala and their role in governing generalized fear in a preclinical rodent model. A chemogenetic approach (DREADDs) was used to inhibit glutamatergic projections from the ACC or vHPC that terminate within the basolateral amygdala (BLA) at recent (1 day) or remote (28 days) time points after contextually fear conditioning male mice. Inactivating ACC or vHPC projections to the BLA significantly reduced generalized fear to a novel, nonthreatening context but had no effect on fear to the training context. Further, our data indicate that the ACC-BLA circuit supports generalization in a time-independent manner. We also identified for the first time a strictly time-dependent role of the vHPC-BLA circuit in supporting remote generalized contextual fear. Dysfunctional signaling to the amygdala from the ACC or the hippocampus could underlie over-generalized fear responses that are associated with anxiety disorders. Our findings demonstrate that the ACC and vHPC regulate fear expressed in novel, nonthreatening environments via projections to the BLA but do so as a result of training intensity or time, respectively.\n\nSignificance StatementAnxiety disorders are characterized by a common symptom that promotes overgeneralization of fear in non-threatening environments. Dysregulation of the amygdala, anterior cingulate cortex (ACC), or hippocampus has been hypothesized to contribute to increased fear associated with anxiety disorders. Our findings show that the ACC and HPC projections to the basolateral amygdala regulate generalized fear in non-threatening, environments. However, descending ACC projections control fear generalization independent of time, whereas HPC projections play a strictly time-dependent role in regulating generalized fear. Thus, dysfunctional ACC/HPC signaling to the BLA may be a predominant underlying mechanism of non-specific fear associated with anxiety disorders. Our data have important implications for predictions made by theories about aging memories and interactions between the hippocampus and cortical regions.

neuroscience↗