Biology subjects

Matovic, S.

Publications and source records attributed to Matovic, S..

3 recordsLinked to original sources

bioRxiv2024

Spike frequency adaptation in primate lateral prefrontal cortex neurons results from interplay between intrinsic properties and circuit dynamics

Recordings of cortical neurons isolated from brain slices and dissociated from their networks, display intrinsic spike frequency adaptation (I-SFA) to a constant current input. Interestingly, extracellular recordings in behaving subjects also show extrinsic-SFA (E-SFA) in response to sustained visual stimulation. Because neurons are isolated from brain networks in slice recordings, it is challenging to infer how I-SFA contributes to E-SFA in interconnected brains during behavior. To investigate this, we recorded responses of macaque lateral prefrontal cortex neurons in vivo during a visually guided saccade task and in acute brain slices in vitro. Broad spiking (BS) putative pyramidal cells and narrow spiking (NS) putative inhibitory interneurons exhibited E-SFA in vivo. In acute brain slices, both cell types displayed I-SFA though their magnitudes differed. To investigate how in vitro I-SFA contributes to in vivo E-SFA, we developed a data-driven hybrid circuit model in which local NS neurons are driven by BS input. We observed that model NS cell responses show longer SFA than observed in vivo. Introducing inhibition of NS cells to the model circuit removed this discrepancy. Our results indicate that both I-SFA and inhibitory circuit dynamics contribute to E-SFA in LPFC neurons. They highlight the contribution of single neuron and network dependent computations to neural activity underlying behavior.

neuroscience↗

bioRxiv2020

Chronic hM3Dq signaling in microglia ameliorates neuroinflammation in male mice

Microglia express muscarinic G protein-coupled receptors (GPCRs) that sense cholinergic activity and are activated by acetylcholine to potentially regulate microglial functions. Knowledge about how distinct types of muscarinic GPCR signaling regulate microglia function in vitro and in vivo is still poor, partly due to the fact that some of these receptors are also present in astrocytes and neurons. We generated mice expressing the hM3Dq Designer Receptor Exclusively Activated by Designer Drugs (DREADD) selectively in microglia to investigate the role of muscarinic M3Gq-linked signaling. We show that activation of hM3Dq using clozapine N-oxide (CNO) elevated intracellular calcium levels and increased phagocytosis of FluoSpheres in vitro. Acute treatment with CNO in vivo did not affect male mouse behavior, however chronic CNO treatment decreased sickness behavior triggered by lipopolysaccharide (LPS) treatment. Interestingly, whereas acute treatment with CNO increased synthesis of cytokine mRNA, chronic treatment attenuated LPS-induced cytokine mRNA changes in the brain, likely explaining the improvement in sickness behavior by chronic hM3Dq activation. No effect of CNO was observed in DREADD-negative mice. These results suggest that chronic activation of M3 muscarinic receptors (the hM3Dq progenitor) in microglia, and potentially other Gq-coupled GPCRs, preconditions microglia to decrease their response to further immunological challenges. Our results indicate that hM3Dq can be a useful tool to modulate neuroinflammation and study microglial immunological memory in vivo, which may be applicable for manipulations of neuroinflammation in neurodegenerative and psychiatric diseases. HighlightsO_LIMicroglial function was manipulated by specific activation of hM3Dq signaling. C_LIO_LIChronic hM3Dq activation prevented LPS-induced sickness behavior in mice. C_LIO_LIMicroglial hM3Dq signaling modulated expression of pro-inflammatory cytokines. C_LI

neuroscience↗

bioRxiv2019

Stress-induced neuronal hypertrophy decreases the intrinsic excitability in stress habituation

A rapid activation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark stress response to an imminent threat, but its chronic activation can be detrimental. Thus, the long-term survival of animals requires experience-dependent fine-tuning of the stress response. However, the cellular mechanisms underlying the ability to decrease the stress responsiveness of the HPA axis remain largely unsolved. Using a stress habituation model in male mice and slice patch-clamp electrophysiology, we studied hypothalamic corticotropin-releasing hormone neurons that form the apex of the HPA axis. We found that the intrinsic excitability of these neurons substantially decreased after daily repeated restraint stress in a time course that coincided with their loss of stress responsiveness in vivo. This plasticity of intrinsic excitability co-developed with an expansion of surface membrane area, resulting in an increase in input conductance with minimal changes in conductance density. Moreover, multi-photon and electron microcopy data found that repeated stress augmented ruffling of the plasma membrane, suggesting an ultrastructural plasticity that efficiently accommodates membrane area expansion with proportionally less expansion of gross cell volume. Overall, we report a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response.\n\nSignificance statementThe long-term survival of animals requires experience-dependent fine-tuning of stress response. Using a mouse model of repeated stress that develops habituation of the hypothalamic-pituitary-adrenal (HPA) axis, our study demonstrates a robust decrease in the intrinsic excitability of the output neuroendocrine neurons of the HPA axis. Mechanistically, we show that repeated stress increases the cell size of these neurons (i.e. surface membrane area). This cell-size change increases input conductance, and hence decreases excitability. Our findings challenge a conventional view that plasticity of intrinsic excitability relies on changes on membrane excitability resulting from up- and down-regulation of various voltage-gated ion channels. Our study reports a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response.

neuroscience↗