Biology subjects

Birnie, M. T.

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

9 recordsLinked to original sources

bioRxiv2026

Disrupted neuropeptide-signaling drives enduring reward deficits after early-life stress

Whereas brain systems mediating acute stress are essential for survival, chronic early-life stress (ELA) may lead to poor ability to experience pleasure (anhedonia), a core feature of depression. For decades, the stress neuropeptide corticotropin-releasing hormone (CRH) has been a target for treating depression. However the failure of several clinical trials blocking CRH receptor1 (CRHR1) has left the therapeutic role of CRH signaling a major unresolved mystery. Here, we uncover the signaling plasticity behind this enigma with the use of in vivo G protein-coupled activation-based (GRAB) imaging and viral-genetic and pharmacological mechanistic manipulations. We find that CRH signaling via CRHR1 indeed disrupts reward behaviors in control mice, but is disrupted in anhedonic mice with a history of ELA. Instead, activation of CRH receptor 2 (CRHR2) reverses anhedonia-like behaviors in adult ELA mice. These findings redefine our understanding of stress-mediated anhedonia and provide a precise, novel therapeutic target for stress-related mental illness.

neuroscience↗

bioRxiv2026

Peptide signaling in the paraventricular thalamus contributes to disrupted adult reward behaviors after early-life adversity

Early-life adversity (ELA) is strongly linked to emotional disorders characterized by dysregulated reward behaviors including diminished motivation for and enjoyment of rewards (anhedonia). However, how transient ELA leads to enduring disruptions of reward behaviors remains unclear. Using activity-dependent genetic labeling during ELA, we previously found that the paraventricular thalamic nucleus (PVT) uniquely distinguishes ELA from typical rearing, and inhibiting ELA-activated PVT cells in adult ELA mice rescued reward behaviors in a sex-specific manner. However, the cellular mechanisms by which ELA alters the function of PVT neurons enduringly, to impact adult reward behaviors is unresolved. Here, we probed potential gene expression mechanisms by assessing reward-induced gene translation selectively in early-life activated (TRAPed) PVT cells, and identified genes regulated by reward in a sex-specific way. Combining data- and hypothesis-driven approaches, we targeted the corticotropin-releasing hormone receptor type 1 (CRHR1) as potentially mediating ELA-induced disruptions of reward behaviors. We find that CRISPR-Cas9-mediated Crhr1 deletion in TRAPed-PVT cells restores typical reward behaviors in ELA mice. Our results provide insight into the developmental origin of mental illness and identify potentially powerful molecular targets for prevention or mitigation of the consequences of ELA on reward behaviors germane to human mental illness.

neuroscience↗

bioRxiv2025

Perirhinal cortex structure and function is dysregulated by corticosteroid treatment

Glucocorticoids play a crucial role in the stress response and in the regulation of circadian function, as well as cognitive, cardiovascular, metabolic and immunological processes. While synthetic glucocorticoids (sGC) are widely used in treating inflammatory disorders, their impact on cognitive functions, which include memory deficits and dysregulation of mood, remains less understood. Here, we demonstrate that chronic treatment with the sGC methylprednisolone (MPL) dysregulates the synaptic proteome and impairs cognitive function in the perirhinal cortex, a region critical for recognition memory and visual perception. Further, we show that synaptic structure and plasticity are altered by MPL treatment, highlighting the mechanisms through which sGCs disrupt mnemonic processing. These results may have broad implications for understanding the cognitive side effects of widely used sGC treatments.

neuroscience↗

bioRxiv2024

Sex-and Stress-Dependent Plasticity of a Corticotropin Releasing Hormone / GABA Projection from the Basolateral Amygdala to Nucleus Accumbens that Mediates Reward Behaviors

BackgroundMotivated behaviors are executed by refined brain circuits. Early-life adversity (ELA) is a risk for human affective disorders involving dysregulated reward behaviors. In mice, ELA causes anhedonia-like behaviors in males and augmented reward motivation in females, indicating sex-dependent disruption of reward circuit operations. We recently identified a corticotropin-releasing hormone (CRH) expressing GABAergic projection from basolateral amygdala (BLA) to nucleus accumbens (NAc) that governs reward-seeking deficits in adult ELA males--but not females. MethodsTo probe the sex-specific role of this projection in reward behaviors, adult male and female CRH-Cre mice raised in control or ELA conditions received excitatory or inhibitory Cre-dependent DREADDs in BLA, and then clozapine N-oxide or vehicle to NAc medial shell during reward behaviors. We determined the cell identity of the projection using immunostaining and electrophysiology. Using tissue clearing, light sheet fluorescence microscopy and deep learning pipelines, we mapped brain-wide BLA CRH+ axonal projections to uncover sex differences in innervation. ResultsChemogenetic manipulations in male mice demonstrated inhibitory effects of the CRH+ BLA-NAc projection on reward behaviors, whereas neither excitation nor inhibition influenced female behaviors. Molecular and electrophysiological cell-identities of the projection did not vary by sex. By contrast, comprehensive whole-brain mapping uncovered significant differences in NAc innervation patterns that were both sex and ELA-dependent, as well as selective changes of innervation of other brain regions. ConclusionsThe CRH/GABA BLA-NAc projection that influences reward behaviors in males differs structurally and functionally in females, uncovering potential mechanisms for the profound sex-specific impacts of ELA on reward behaviors.

neuroscience↗

bioRxiv2024

Paraventricular Thalamus Neuronal Ensembles Encode Early-life Adversity and Mediate the Consequent Sex-dependent Disruptions of Adult Reward Behaviors

While links between early-life adversity (ELA) and mental illnesses characterized by dysregulated reward behaviors are well-established, the underlying mechanisms remain unclear. In mice, ELA reduces hedonic consumption and interest in sex reward in adult males and, in contrast, augments reward consumption in females. Here, using genetic tagging (TRAPing) we found robust, sex-specific activation of thalamic paraventricular nucleus (PVT) neurons during ELA. Manipulating these neurons in adults normalized reward behaviors: Blocking TRAPed anterior PVT neurons restored hedonic consumption in ELA males and augmented hedonic consumption in control females. In contrast, activation of these neurons reduced consumption in control males and ELA females. For posterior PVT, blocking TRAPed cells attenuated excessive reward consumption in ELA females and reduced it in control males. Thus, PVT is key for adaptive brain plasticity; anterior and posterior PVT carry different functions and contribute to the effects of ELA on adult reward behaviors in a sex-dependent manner.

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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.

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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.

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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↗