Biology subjects

Sargin, D.

Publications and source records attributed to Sargin, D..

4 recordsLinked to original sources

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

Medial Prefrontal Cortex Serotonin Input Regulates Cognitive Flexibility in Mice

The medial prefrontal cortex (mPFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin project to the mPFC, and serotonergic drugs influence emotion and cognition. Yet, the specific roles of endogenous serotonin release in the mPFC on neurophysiology and behavior are unknown. We show that axonal serotonin release in the mPFC directly inhibits the major mPFC output neurons. In serotonergic neurons projecting from the dorsal raphe to the mPFC, we find endogenous activity signatures pre-reward retrieval and at reward retrieval during a cognitive flexibility task. In vivo optogenetic activation of this pathway during pre-reward retrieval selectively improved extradimensional rule shift performance while inhibition impaired it, demonstrating sufficiency and necessity for mPFC serotonin release in cognitive flexibility. Locomotor activity and anxiety-like behavior were not affected by either optogenetic manipulation. Collectively, our data reveal a powerful and specific modulatory role of endogenous serotonin release from dorsal raphe-to-mPFC projecting neurons in cognitive flexibility.

neuroscience↗

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↗