Biology subjects

Birnie, M. T.

Publications and source records attributed to Birnie, M. T..

4 recordsLinked to original sources

bioRxiv2022

Genetic tagging uncovers a robust, selective activation of the thalamic paraventricular nucleus by adverse experiences early in life

BackgroundEarly-life adversity (ELA) is associated with increased risk for mood disorders including depression and substance use disorders. These are characterized by impaired reward-related behaviors, suggesting compromised operations of reward-related brain circuits. However, the brain regions engaged by ELA that mediate these enduring consequences of ELA remain largely unknown. In an animal model of ELA, we have identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits. MethodsEmploying TRAP2 male and female mice, in which neurons activated within a defined timeframe are permanently tagged, we compared ELA and control-reared mice, assessing the quantity and distribution of ELA-related neuronal activation. After validating the TRAP2 results using native cFos labeling, we defined the molecular identity of this population of activated neurons. ResultsWe uniquely demonstrate that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus (PVT) is robustly and almost exclusively activated by ELA and is the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated PVT neurons express CRFR1, the receptor for the stress-related peptide, corticotropin-releasing hormone (CRH), but these neurons do not express CRH itself. ConclusionsWe show here that the PVT, an important component of reward circuits which is known to encode remote, emotionally salient experiences to influence future motivated behaviors, encodes adverse experiences as remote as those occurring during the early postnatal period and is thus poised to contribute to the enduring deficits in reward-related behaviors consequent to ELA.

neuroscience↗

bioRxiv2022

Circadian regulation of hippocampal function is disrupted with chronic corticosteroid treatment

Neuropsychiatric disorders such as major depression and schizophrenia are highly prevalent and contribute substantially to disease burden worldwide. Despite this, progress understanding the pathophysiology has remained largely elusive, yet these disorders often exhibit a loss of regulation of biological rhythms, such as sleep/wake cycles and hormonal rhythms. Cushings disease, a condition characterized by chronic corticosteroid (cortisol) hypersecretion is associated with psychiatric and neurocognitive disorders and disruption to the circadian release of cortisol can result in depression and neurocognitive impairment. In rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity regulation via an intra-hippocampal circadian transcriptional clock. During the early active period, when corticosteroid availability is high, CA1 region excitatory and inhibitory post-synaptic currents were augmented along with long-term potentiation. In contrast, chronic corticosteroid exposure disturbed hippocampal function. The hippocampal transcriptome, as well as circadian regulation of synaptic plasticity were ablated, resulting in memory loss during hippocampal-dependent behavior. These findings identify how exposure to elevated levels of corticosteroid, that is often seen in neuropsychiatric illness, results in adverse critical hippocampal function. These data provide novel insights into the molecular mechanisms of neurocognitive disorders and provides evidence for corticosteroid-mediated intervention in disabling mental illnesses.

neuroscience↗

bioRxiv2022

Stress-induced plasticity of a novel CRH GABA projection disrupts reward behaviors

Disrupted operations of the reward circuit are thought to underlie major emotional disorders including depression and drug abuse1-3. These disorders commonly arise following early life stress4,5; however, how stress early in life enduringly impacts reward circuit functions to promote disease remains unclear. Here, we discover and characterize a novel stress-sensitive reward-circuit projection connecting the basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We then identify a crucial role for this projection in executing the disrupted reward behaviors provoked by early-life adversity (ELA): Chemogenetic and optogenetic stimulations of the CRHGABA BLA[->]NAc projection in typically reared mice suppressed several reward seeking behaviors, recapitulating deficits resulting from ELA and demonstrating a key contribution of this pathway in the normal operations of the reward circuit. Next, inhibition of the CRHGABA BLA[->]NAc projection in adult mice that experienced ELA restored typical reward behaviors in these mice, and, in contrast, had little effect in typically reared mice, indicating a selective ELA-induced maladaptive plasticity of this reward-circuit projection. We discover a novel, stress-sensitive, reward inhibiting projection from the BLA[->]NAc with unique molecular features, which may provide targets for intervention in disabling mental illnesses.

neuroscience↗

bioRxiv2021

Single-Cell transcriptional changes in hypothalamic CRH-expressing neurons after early-life adversity inform enduring alterations in responses to stress

Mental and cognitive health, as well as vulnerability to neuropsychiatric disorders, involve the interplay of genes with the environment, particularly during sensitive developmental periods. Early-life stress / adversity (ELA) promotes vulnerabilities to stress-related affective disorders, yet it is unknown how a transient ELA dictates life-long neuroendocrine and behavioral reactions to stress. The population of hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons that regulate stress-responses is a promising candidate to mediate the enduring influences of ELA on stress-related behavioral and hormonal responses via enduring transcriptional and epigenetic mechanisms. Capitalizing on a well-characterized model of ELA, we examined here the ELA-induced changes in gene expression profiles of stress-sensitive CRH-neurons in the hypothalamic paraventricular nucleus (PVN) of male mice. Given the known heterogeneity of these neuronal populations, we employed single-cell RNA sequencing (RNA-seq) approaches. The use of single-cell transcriptomics identified distinct CRH-expressing neuronal populations characterized by both their gene expression repertoire and their neurotransmitter profiles. Expression changes provoked by ELA clustered around genes involved in neuronal differentiation, synapse formation, altered energy metabolism and the cellular responses to stress and injury. Notably, the ELA-induced transcriptional changes took place primarily in subpopulations of glutamatergic CRH cells. Finally, ELA-induced transcriptional reprogramming of hypothalamic CRH-expressing neurons heralded significant, enduring disruptions of both hormonal and behavioral responses to stress throughout life.

neuroscience↗