Biology subjects

Kunwar, P. S.

Publications and source records attributed to Kunwar, P. S..

3 recordsLinked to original sources

bioRxiv2025

GPR34 regulation of disease-associated microglial states and responses to physiological stimuli

Expression of the G protein coupled receptor GPR34 is highly enriched in microglia and has been reported to be downregulated in several brain disease contexts, including Alzheimers disease (AD) and multiple sclerosis (MS). GPR34 function is poorly understood, as is its role in regulation of microglial states. Using RNA-sequencing, we find that microglia from Gpr34 knockout (KO) mouse brains exhibited a transcriptomic shift toward disease-associated microglia (DAM) and inflammatory profiles, partially resembling the microglial phenotype seen in 5xFAD AD model mice. Moreover, when Gpr34 KO mice were crossed with 5xFAD mice, the DAM transcriptional profile of microglia and glial pathology were further enhanced beyond the already robust DAM signature driven by 5xFAD alone. This occurred without affecting amyloid plaque burden. Human stem cell-derived microglia (iMGLs) lacking GPR34 showed reduced calcium (Ca{superscript 2}) and phosphorylated ERK (pERK) signaling in response to stimulation with known GPR34 agonists (lyso-phosphatidylserine (lysoPS) and myelin), as well as transcriptomic changes in immune regulation and cell proliferation related pathways. Interestingly, GPR34 KO iMGLs were selectively impaired in phagocytosis of myelin but not amyloid-{beta} (A{beta}) or E. coli, and showed a diminished transcriptional response elicited by myelin. Together, these findings suggest that GPR34 is important for maintaining microglia in a homeostatic state, promotes phagocytosis of and transcriptional response to myelin, and limits microglial activation in neurodegenerative disease conditions.

neuroscience↗

bioRxiv2025

Altered striatal dopamine dynamics and behavior in Grin2a mutant mice, a genetic mouse model of schizophrenia

Schizophrenia (SCZ), a complex psychiatric disorder with a strong genetic basis, is thought to involve, at least in part, dopamine dysregulation in the striatum. Recent large-scale exome sequencing has identified multiple SCZ risk genes, including GRIN2A (encoding an NMDA (N-methyl-D-aspartate) receptor subunit) and AKAP11 (encoding a protein kinase A binding protein), which is also a risk gene for bipolar disorder (BD). However, the mechanisms by which these genetic risk factors perturb dopamine circuits and cause psychotic symptoms remain poorly understood. We asked how behavior, dorsomedial striatal dopamine (DA) dynamics and the activity of D1-/D2-spiny projection neurons (SPNs) were altered in Grin2a and Akap11 mutants. In the open field, Grin2a knockout mice display hyperlocomotion and an abnormal organization of naturalistic behaviors. They also displayed heightened behavioral responses to objects and auditory stimuli. Grin2a heterozygous animals mostly showed intermediate phenotypes, suggesting a dose-dependent effect of Grin2a loss. Further, Grin2a knockout mutants exhibited aberrant dopamine events, altered coupling of dopamine with locomotor features, and exaggerated stimuli-evoked dopamine responses. Notably, heterozygous animals also showed altered striatal SPN events in the open field reflecting dysregulated neural activity in both dSPNs and iSPNs. Compared to Grin2a mutants, Akap11 mutants displayed opposite phenotypes, showing reduced locomotion with a shift from high- to low-velocity movement and distinct alterations in striatal neural activity. Together, GRIN2A (SCZ risk) and AKAP11 (BD/SCZ risk) mutations induce different, often opposite, effects on striatal dopamine signaling and behavior, suggesting that these two risk genes act through distinct mechanisms.

neuroscience↗

bioRxiv2019

Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

Persistent neural activity has been described in cortical, hippocampal, and motor networks as mediating short-term working memory of transiently encountered stimuli1-4. Internal emotion states such as fear also exhibit persistence following exposure to an inciting stimulus5,6, but such persistence is typically attributed to circulating stress hormones7-9; whether persistent neural activity also plays a role has not been established. SF1+/Nr5a1+ neurons in the dorsomedial and central subdivision of the ventromedial hypothalamus (VMHdm/c) are necessary for innate and learned defensive responses to predators10-13. Optogenetic activation of VMHdmSF1 neurons elicits defensive behaviors that can outlast stimulation11,14, suggesting it induces a persistent internal state of fear or anxiety. Here we show that VMHdmSF1 neurons exhibit persistent activity lasting tens of seconds, in response to naturalistic threatening stimuli. This persistent activity was correlated with, and required for, persistent thigmotaxic (anxiety-like) behavior in an open-field assay. Microendoscopic imaging of VMHdmSF1 neurons revealed that persistence reflects dynamic temporal changes in population activity, rather than simply synchronous, slow decay of simultaneously activated neurons. Unexpectedly, distinct but overlapping VMHdmSF1 subpopulations were persistently activated by different classes of threatening stimuli. Computational modeling suggested that recurrent neural networks (RNNs) incorporating slow excitation and a modest degree of neurochemical or spatial bias can account for persistent activity that maintains stimulus identity, without invoking genetically determined \"labeled lines\"15. Our results provide causal evidence that persistent neural activity, in addition to well-established neuroendocrine mechanisms, can contribute to the ability of emotion states to outlast their inciting stimuli, and suggest a mechanism that could prevent over-generalization of defensive responses without the need to evolve hardwired circuits specific for each type of threat.

neuroscience↗