Biology subjects

Riga, D.

Publications and source records attributed to Riga, D..

4 recordsLinked to original sources

bioRxiv2023

Neuropeptide Y neurons of the locus coeruleus inhibit noradrenergic system activity to reduce anxiety

Abstract / SummaryAdaptive responses to challenging environments depend on optimal function of the locus coeruleus (LC), the brains main source of noradrenaline and primary mediator of the initial stress response. Built-in systems that exert regulatory control over the LC are largely unidentified. A good candidate system is neuropeptide Y (NPY), which is traditionally linked to anxiety-relief. Currently, the endogenous source of NPY to the LC, and how NPY-expressing neurons modulate the noradrenergic system to regulate anxiety remain unclear. We here identify, in mice, a novel NPY-expressing neuronal population (peri-LCNPY) neighboring LC noradrenergic neurons that locally innervates the pericoerulean space. Moreover, we demonstrate that stress engages peri-LCNPY neurons, increasing their excitability. Mimicking peri-LCNPY neuronal activation using ex vivo chemogenetics suppresses LC noradrenergic neuron activity, via an NPY Y1 receptor-mediated mechanism. Furthermore, in vivo chemogenetic stimulation of peri-LCNPY neurons results in Y1R-dependent anxiety-relief. Conversely, inhibiting peri-LCNPY neurons increases anxiety-like behaviors. Together, we establish a causal role for peri-LCNPY-mediated neuromodulation of the LC in the regulation of anxiety, providing novel insights in the endogenous mechanisms underlying adaptive responses to adversity.

neuroscience↗

bioRxiv2022

Molecular Signatures and Cellular Diversity During Mouse Habenula Development

The habenula plays a key role in various motivated and pathological behaviors and is composed of molecularly distinct neuron subtypes. Despite progress in identifying mature habenula neuron subtypes, how these subtypes develop and organize into functional brain circuits remains largely unknown. Here we performed single-cell transcriptional profiling of mouse habenular neurons at critical developmental stages instructed by detailed three-dimensional anatomical data. Our data reveal cellular and molecular trajectories during embryonic and postnatal development leading to different habenular subtypes. Further, based on this analysis our work establishes the distinctive functional properties and projection target of a previously uncharacterized subtype of Cartpt+ habenula neurons. Finally, we show how comparison of single-cell transcriptional profiles and GWAS data links specific developing habenular subtypes to psychiatric disease. Together, our study begins to dissect the mechanisms underlying habenula neuron subtype-specific development and creates a framework for further interrogation of habenular development in normal and disease states.

developmental biology↗

bioRxiv2019

From stress to depression: Development of extracellular matrix-dependent cognitive impairment following social stress

Stress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. To shed light on this stress-to-depression transition process, we profiled the development of an enduring depressive-like state in rat by assessing affective behavior and hippocampal function during the 2 months following social defeat stress. In addition, we measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during a sustained depressive-like state. We found affective disturbance and cognitive impairment to develop disparately after social stress. While affective deficits emerged gradually, spatial memory impairment was present both early after stress and during the late-emerging chronic depressive-like state. Surprisingly, these phases were separated by a period of normalized hippocampal function. Similarly, the SDPS paradigm induced a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Early after stress, synaptic ECM proteins and the number of perineuronal nets enwrapping parvalbumin-expressing interneurons were decreased. This was followed by a recovery period without ECM dysregulation, before subsequent decreased metalloproteinase activity and ECM build-up, previously shown to impair memory. This suggests that intact hippocampal function requires unaltered ECM levels. Together our data 1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, 2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and 3) support a role of the ECM in mediating long-lasting memory-effects of social stress.

neuroscience↗

bioRxiv2018

Stress vulnerability promotes an alcohol prone phenotype in a preclinical model of sustained depression

Major depression and alcohol-related disorders frequently co-occur. Depression severity weighs on the magnitude and persistence of comorbid alcohol use disorder (AUD), with severe implications for disease prognosis. Here, we investigated whether depression vulnerability drives propensity to AUD at the preclinical level. We used the social defeat-induced persistent stress (SDPS) model of chronic depression in combination with operant alcohol self-administration (SA). Male Wistar rats were subjected to social defeat (5 episodes) and prolonged social isolation (~12 weeks) and subsequently classified as SDPS-prone or SDPS-resilient based on their affective and cognitive performance. Using an operant alcohol SA paradigm, acquisition, motivation, extinction and cue-induced reinstatement of alcohol-seeking were examined in the two subpopulations. SDPS-prone animals showed increased alcohol SA, excessive motivation to acquire alcohol, persistent alcohol-seeking despite alcohol unavailability, extinction resistance and increased cue-induced relapse; the latter could be blocked by the 2 adrenoreceptor agonist guanfacine. In SDPS-resilient rats, prior exposure to social defeat increased alcohol SA without affecting any other measures of alcohol-seeking and -taking. Our data revealed that depression proneness confers vulnerability to alcohol, emulating patterns of alcohol dependence seen in human addicts, and that depression resilience to a large extent protects from the development of AUD-like phenotypes. Furthermore, our data suggest that stress exposure alone, independently of depressive symptoms, alters alcohol intake in the long-term.

animal behavior and cognition↗