Biology subjects

Vaidya, V. A.

Publications and source records attributed to Vaidya, V. A..

15 recordsLinked to original sources

bioRxiv2026

Serotonin2A receptors in the medial prefrontal cortex do not drive DOI-induced head-twitch responses in rodents

Background The head-twitch response (HTR) is a serotonin2A receptor (5-HT2AR) dependent behavioral correlate of serotonergic psychedelic action in rodent models. Although cortical 5-HT2ARs have been implicated in HTRs, the contribution of specific cortical circuits to this behavior remains poorly defined, with a few reports implicating the medial prefrontal cortex (mPFC) in the generation of HTRs. Results The serotonergic psychedelic, 2,5-dimethoxy-4-iodoamphetamine (DOI), induced head-twitch responses (HTRs) in male and female rats and mice, with sex differences noted only in mice. DOI also increased ear-scratch responses (ESRs), and reduced digging and grooming behaviors only in mice. While the DOI-evoked HTRs and ESRs were absent in 5-HT2AR knock-out (5-HT2AR KO) mice, reduced digging and grooming occurred in both wild-type and 5-HT2AR KO mice. We assessed the role of 5-HT2ARs in the mPFC in regulating DOI-induced HTRs using pharmacological and genetic approaches. Targeted DOI microinfusion into the mPFC did not induce HTRs in rats, in contrast to the robust increase in HTRs noted following systemic DOI administration. Local delivery of the selective 5-HT2AR antagonist, MDL100907, into the mPFC also had no effect on the systemic DOI-evoked increase in HTRs in rats. Experiments capitalizing on genetic strategies to perturb 5-HT2AR expression in the mPFC, indicated that viral restoration of 5-HT2AR expression in mPFC CaMKII-positive excitatory neurons was not sufficient to reinstate DOI-evoked HTRs or ESRs in 5-HT2AR KO mice. Further, conditional 5-HT2AR deletion in CaMKII-positive excitatory neurons in the mPFC did not alter systemic DOI-induced HTRs and ESRs in mice. Conclusions These findings indicate that the serotonergic psychedelic DOI induces species- and sex-specific behavioral effects in rodent models, with a robust 5-HT2AR dependence noted for DOI-evoked HTRs and ESRs. Further, we show that 5-HT2ARs in the mPFC do not appear to contribute to the enhanced HTRs and ESRs elicited by DOI.

neuroscience↗

bioRxiv2026

Early-life stress-induced gut dysbiosis is ameliorated by nicotinamide treatment

Early life stress (ELS) in the form of adverse experiences in childhood results in multiple psycho-physiological pathologies during adulthood and accelerates aging. Such pathologies are recently observed to be alleviated upon nicotinamide treatment in a maternal separation model of ELS. We report a nicotinamide-driven amelioration of gut dysbiosis in middle-aged rodents with a history of neonatal maternal separation.

microbiology↗

bioRxiv2026

Chronic postnatal chemogenetic activation of forebrain excitatory neurons modulates adult glial function and metabolism in male mice

Early adversity increases vulnerability for adult psychopathology. Across multiple pre-clinical models of early adversity, there are reports of glial dysfunction and disrupted amino acid neurotransmission, along with maladaptive behavioral responses in adulthood. Disrupted G-protein coupled receptor signaling is known to phenocopy specific consequences of early life adversity. Enhanced Gq signaling in the forebrain excitatory neurons in early postnatal life programs anxio-depressive behaviors in adulthood, accompanied by altered neuronal glutamate and GABA metabolism in mouse models. We hypothesized that enhancing Gq signaling in forebrain excitatory neurons in early postnatal life may also impact glial function in adulthood. Our results show that postnatal hM3Dq-mediated chemogenetic activation of CaMKII-positive forebrain excitatory neurons not only increases anxiety-like behavior, but also evokes bidirectional transcriptional regulation of multiple glia-associated genes in the neocortex and hippocampi. While Gfap, Aldh1l1, S100{beta}, Eaat1, Eaat2 and Eaat3, mRNA levels were reduced in the neocortex, they were enhanced in the hippocampus, and a similar pattern was noted for GFAP protein levels. Transient, postnatal chemogenetic activation of CaMKII-positive neurons did not alter astrocyte cell density in both the neocortex and the hippocampus. Using (1H-(13C)) NMR spectroscopy, we observed a significant decline in astrocyte-specific glutamate and GABA neurotransmitter turnover, and a reduction in astrocyte metabolic flux within the neocortex and the hippocampus in adulthood in animals with a history of postnatal chemogenetic activation of forebrain excitatory neurons. Our findings indicate that chemogenetically driving Gq signaling transiently during the postnatal window in forebrain excitatory neurons results in persistent changes well into adulthood, with enhanced anxiety-like behaviors and disrupted glial function and metabolism, phenocopying specific changes in glial function noted following early adversity.

neuroscience↗

bioRxiv2024

A Cell-Permeable Fluorescent Probe Reveals Temporally Diverse PI(4,5)P2 Dynamics Evoked by Distinct GPCR Agonists in Neurons

Lipids, key constituents of cell-membranes, are the first responders to cell signals. At the crux of spatiotemporal dynamics of lipid-signaling response are phosphoinositides. Indeed, phosphoinositides like phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2), present in the inner-leaflet of eukaryotic cell-membranes, form the link between signal reception and downstream signal-transmission. In this backdrop, reversible fluorescent probes that can track live PI(4,5)P2 dynamics on a seconds time-scale will afford key insights into lipid-mediated signaling. However, realizing cell-permeable PI(4,5)P2-selective sensors for imaging dynamics remains a challenge due to the presence of structurally similar lipids and low levels of PI(4,5)P2. We report a computationally-designed, rapid-response, reversible, photo-stable, fluorescent sensor that permeates living cells, neurons, and a multicellular organism within few min of direct incubation and distinctly visualizes PI(4,5)P2 pools. We used the sensor to interrogate the role of PI(4,5)P2 in driving heterogeneity of signaling responses and contrasting behavioral effects that ensue upon binding of distinct ligands to the same G protein-coupled receptor. Specifically, we asked whether probing PI(4,5)P2 dynamics using our novel sensor could uncover the earliest of signaling differences evoked by hallucinogenic versus non-hallucinogenic ligands at the serotonin2A (5-HT2A) receptor. Our results reveal that a hallucinogenic ligand at the 5-HT2A receptor leads to a slower rate of PI(4,5)P2-depletion when compared to a non-hallucinogenic ligand, within the initial seconds of ligand addition, but has a sustained effect. The ability of our designer chemical probe in timing early seconds-minute timescale lipid-dynamics in living cells opens avenues for tracking early time-point molecular events in neuronal response to chemical and physical stimuli.

biochemistry↗

bioRxiv2023

Fluoxetine treatment during postnatal and juvenile temporal epochs evokes diametrically opposing changes in anxio-depressive behaviors, gene expression, mitochondrial function, and neuronal architecture in the medial prefrontal cortex

BackgroundThe selective serotonin reuptake inhibitor, fluoxetine is reported to evoke distinct effects on anxio-depressive behaviors based on the temporal window of administration. Here, we systematically addressed the influence of postnatal or juvenile fluoxetine treatment on anxio-depressive behavior, gene expression, mitochondrial biogenesis, and neuronal cytoarchitecture in adulthood. MethodsRat pups received postnatal fluoxetine (PNFlx) or juvenile fluoxetine (JFlx) treatment from postnatal day 2 (P2)-P21 or P28-48 respectively, and were assessed for changes in anxio-depressive behaviors, global gene expression, mitochondrial biogenesis/function, and dendritic cytoarchitecture in the medial prefrontal cortex (mPFC) in adulthood. ResultsPNFlx evoked long-lasting increases in anxio-depressive behaviors, whereas JFlx elicited persistent decreases in anxio-depressive behavior, accompanied by differential and minimally overlapping transcriptional changes in the mPFC in adulthood. We noted opposing changes in mitochondrial function and dendritic cytoarchitecture in the mPFC of PNFlx and JFlx animals, with a decline observed following PNFlx and an increase in response to JFlx treatment. Furthermore, the enhanced despair-like behavior in the PNFlx cohort was reversed by adult-onset treatment with nicotinamide, a precursor for NAD+ which enhances mitochondrial bioenergetics. ConclusionsFluoxetine treatment in early postnatal versus juvenile windows evokes opposing and persistent effects on anxio-depressive behavior in adult male rats, along with differential effects on gene expression, mitochondrial function, and dendritic morphology in the mPFC. Collectively, our findings highlight two distinct temporal windows in which fluoxetine exposure programs starkly differing outcomes in mood-related behavior, and posits a role for altered bioenergetics within the mPFC in contributing to these distinctive changes in emotionality.

neuroscience↗

bioRxiv2023

Chronic chemogenetic activation of hippocampal progenitors enhances adult neurogenesis and modulates anxiety-like behavior and fear extinction learning

Adult hippocampal neurogenesis is a lifelong process that involves the integration of newborn neurons into the hippocampal network, and plays a role in cognitive function and the modulation of mood-related behavior. Here, we sought to address the impact of chemogenetic activation of adult hippocampal progenitors on distinct stages of progenitor development, including quiescent stem cell activation, progenitor turnover, differentiation and morphological maturation. We find that hM3Dq-DREADD-mediated activation of nestin-positive adult hippocampal progenitors recruits quiescent stem cells, enhances progenitor proliferation, increases doublecortin-positive newborn neuron number, accompanied by an acceleration of differentiation and morphological maturation, associated with increased dendritic complexity. Behavioral analysis indicated anxiolytic behavioral responses in transgenic mice subjected to chemogenetic activation of adult hippocampal progenitors at timepoints when newborn neurons are predicted to integrate into the mature hippocampal network. Furthermore, we noted an enhanced fear memory extinction on a contextual fear memory learning task in transgenic mice subjected to chemogenetic activation of adult hippocampal progenitors. Our findings indicate that hM3Dq-DREAD-mediated chemogenetic activation of adult hippocampal progenitors impacts distinct aspects of hippocampal neurogenesis, associated with the regulation of anxiety-like behavior and fear memory extinction.

neuroscience↗

bioRxiv2022

Genetic loss of norepinephrine does not alter adult hippocampal neurogenesis in dopamine β-hydroxylase deficient mice

Norepinephrine (NE), and specific adrenoceptors, have been reported to influence distinct aspects of adult hippocampal neurogenesis, including latent stem cell activation, progenitor proliferation, and differentiation. These findings are predominantly based on the use of pharmacological approaches in both in vitro and in vivo systems. Here, we sought to assess the consequences of genetic ablation of NE on adult hippocampal neurogenesis, by examining dopamine {beta} hydroxylase knockout (Dbh-/-) mice, which lack NE from birth. We find that Dbh-/- mice exhibit no difference in adult hippocampal progenitor proliferation and survival. Further, the number of immature newborn neurons, labeled using stage-specific developmental markers within the hippocampal neurogenic niche, was also unaltered in Dbh -/- mice. In contrast, the noradrenergic neurotoxin DSP-4, which had previously been shown to reduce adult hippocampal neurogenesis in rats, also resulted in a decline in hippocampal progenitor proliferation in C57/Bl6N mice. These findings indicate that pharmacological lesioning of noradrenergic afferents in adulthood, but not the complete genetic loss of NE from birth, impairs adult hippocampal neurogenesis in mice.

neuroscience↗

bioRxiv2022

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

Animal models of early adversity or neurodevelopmental disorders are associated with altered parvalbumin (PV)-positive inhibitory interneuron number and function, correlated with a dysregulated excitation-inhibition (E/I) balance that is implicated in the pathophysiology of neuropsychiatric disorders. We sought to address whether altering neuronal activity of PV-positive interneurons during the postnatal developmental window influences the emergence of anxio-depressive behaviors in adulthood, which are known to be perturbed in models of early adversity and neurodevelopmental disorders. We used a PV-Cre::hM3Dq-DREADD bigenic mouse line that selectively expresses the hM3Dq-DREADD receptor in PV-positive interneurons, and chemogenetically enhanced Gq signaling in PV-positive interneurons during the postnatal window via administration of the DREADD agonist, clozapine-N-oxide. Immunofluorescence studies indicated the selective expression of hM3Dq-DREADD in PV-positive interneurons in limbic circuits, and revealed a reduction in expression of the neuronal activity marker, c-Fos, in these circuits, following chemogenetic hM3Dq-DREADD mediated activation of PV-positive inhibitory interneurons. We noted no change in either growth or sensorimotor reflex milestones following chronic hM3Dq-DREADD mediated chemogenetic activation of PV-positive inhibitory interneurons in postnatal life. Adult male and female PV-Cre::hM3Dq-DREADD bigenic mice with a history of postnatal chemogenetic activation of PV-positive interneurons exhibited a reduction in anxiety and despair-like behavior in adulthood, which was noted in both a behavioral task and sex-dependent manner. These results indicate that altering neuronal activity within PV-positive interneurons during the critical postnatal developmental window can shape the emergence of anxio-depressive behaviors in adulthood, and suggest that interactions with sex as a variable play a key role in determining behavioral outcomes.

neuroscience↗

bioRxiv2021

The hallucinogenic serotonin2A receptor agonist, DOI, promotes CREB-dependent gene expression of specific plasticity-associated genes in the rodent neocortex

Psychedelic compounds that target the 5-HT2A receptor are reported to evoke psychoplastogenic effects, including enhanced dendritic arborization and synaptogenesis. Transcriptional regulation of neuronal plasticity-associated genes is implicated in the cytoarchitectural effects of serotonergic psychedelics, however the transcription factors that drive this regulation are poorly elucidated. Here, we addressed the contribution of the transcription factor cAMP response element binding protein (CREB) in the regulation of neuronal plasticity-associated genes by the hallucinogenic 5-HT2A receptor agonist, DOI. In vitro studies with rat cortical neurons indicated that DOI enhances the phosphorylation of CREB (pCREB) through the MAP kinase and CaMKII pathways, with both cascades contributing to the DOI-evoked upregulation of Arc, Bdnf1, Cebpb and Egr2 expression, whilst the upregulation of Egr1 and cFos mRNA involved the MAP kinase and CaMKII pathway respectively. We observed a robust DOI-evoked increase in the expression of several neuronal plasticity-associated genes in the rat neocortex in vivo. Further, 5-HT2A receptor stimulation enhanced pCREB enrichment at putative cAMP response element (CRE) binding sites in the Arc, Bdnf1, Cebpb, cFos, but not Egr1 and Egr2, promoters in the rodent neocortex. The DOI-mediated transcriptional induction of Arc, cFos and Cebpb was significantly attenuated in the neocortex of CREB deficient (CREB{delta} KO) mice. Collectively, these results indicate that the hallucinogenic 5-HT2A receptor agonist DOI leads to a rapid transcriptional upregulation of several neuronal plasticity-associated genes, with a subset of them exhibiting a CREB-dependent regulation. Our findings raise the intriguing possibility that similar to slow-acting classical antidepressants, rapid-action serotonergic psychedelics that target the 5-HT2A receptor may also recruit the transcription factor CREB to enhance the expression of neuronal plasticity-associated genes in the neocortex, which could in turn contribute to the rapid psychoplastogenic changes evoked by these compounds.

neuroscience↗

bioRxiv2021

Chronic hM4Di-DREADD mediated chemogenetic inhibition of forebrain excitatory neurons in postnatal or juvenile life does not alter adult mood-related behavior

G-protein coupled receptors (GPCRs) coupled to Gi-signaling, in particular downstream of monoaminergic neurotransmission, are posited to play a key role during developmental epochs (postnatal and juvenile), in shaping the emergence of adult anxio-depressive behaviors and sensorimotor gating. To address the role of Gi-signaling in these developmental windows, we used a CamKII-tTA::TRE hM4Di bigenic mouse line to express the hM4Di-DREADD in forebrain excitatory neurons and enhanced Gi-signaling via chronic administration of the DREADD agonist, CNO in the postnatal (PNCNO: postnatal day 2-14) or juvenile (JCNO: postnatal day 28-40) window. We confirmed that the expression of the HA-tagged hM4Di-DREADD was restricted to CamKII-positive neurons in the forebrain, and administration of CNO in postnatal or juvenile windows evoked inhibition in forebrain circuits of the hippocampus and cortex, as indicated by a decline in expression of the neuronal activity marker, c-fos. hM4Di-DREADD mediated inhibition of CamKII-positive forebrain excitatory neurons in postnatal or juvenile life did not impact the weight profile of mouse pups, and also did not influence the normal ontogeny of sensory reflexes. Further, postnatal or juvenile hM4Di-DREADD mediated inhibition of CamKII-positive forebrain excitatory neurons did not alter anxiety or despair-like behaviors in adulthood, and did not impact sensorimotor gating. Collectively, these results indicate that chemogenetic induction of Gi-signaling in CamKII-positive forebrain excitatory neurons in postnatal and juvenile temporal windows does not appear to impinge on the programming of anxio-depressive behaviors in adulthood.

neuroscience↗

bioRxiv2020

Postnatal fluoxetine treatment alters perineuronal net formation and maintenance in the hippocampus

Elevation of serotonin via postnatal fluoxetine (PNFlx) treatment during critical temporal windows is hypothesized to perturb the development of limbic circuits thus establishing a substratum for persistent disruption of mood-related behavior. We examined the impact of PNFlx treatment on the formation and maintenance of perineuronal nets (PNNs), extracellular matrix (ECM) structures that deposit primarily around inhibitory interneurons, and mark the closure of critical period plasticity. PNFlx treatment evoked a significant decline in PNN number, with a robust reduction in PNNs deposited around parvalbumin (PV) interneurons, within the CA1 and CA3 hippocampal subfields at postnatal day 21 in Sprague-Dawley rat pups. While the reduction in CA1 subfield PNN number was still observed in adulthood, we observed no change in colocalization of PV-positive interneurons with PNNs in the hippocampi of adult PNFlx animals. PNFlx treatment did not alter hippocampal parvalbumin, calretinin, or reelin-positive neuron numbers in PNFlx animals at P21 or in adulthood. We did observe a small, but significant increase in somatostatin (SST)-positive interneurons in the DG subfield of PNFlx-treated animals in adulthood. This was accompanied by altered GABA-A receptor subunit composition, increased dendritic complexity of apical dendrites of CA1 pyramidal neurons, and enhanced neuronal activation revealed by increased c-Fos-positive cell numbers within hippocampi of PNFlx-treated animals in adulthood. These results indicate that PNFlx treatment alters the developmental trajectory of PNNs within the hippocampus, raising the possibility of a disruption of critical period plasticity and the establishment of an altered excitation-inhibition balance within this key limbic brain region. Significance StatementClinical and preclinical studies indicate that developmental exposure to fluoxetine programs persistent dysregulation of mood-related behaviors. This is hypothesized to involve the disruption of the normal development of key brain regions, such as the hippocampus that regulate mood behaviors. We show that postnatal exposure to fluoxetine alters hippocampal perineuronal nets (PNNs), extracellular matrix structures that regulate plasticity and mark the closure of critical periods. The decline in PNNs is noted in early postnatal life, and persists into adulthood in specific hippocampal subfields. Adult animals with a history of postnatal fluoxetine exposure exhibit altered numbers of somatostatin interneurons, GABA receptor subunit expression and neuronal activation within the hippocampus. This indicates that postnatal fluoxetine disrupts the normal developmental trajectory of the hippocampus.

neuroscience↗

bioRxiv2020

Receptor-independent membrane mediated pathways of serotonin action

Serotonin is a neurotransmitter as well as a somatic signaling molecule, and the serotonergic system is a major target for psychotropic drugs. Serotonin, together with a few related neurotransmitters, has recently been found to exhibit an unexpectedly high lipid membrane affinity1–3. It has been conjectured that extrasynaptic serotonin can diffuse in the lipid membrane to efficiently reach remote receptors (and receptors with buried ligand-binding sites)4, providing a mechanism for the diffuse ‘volume’ neurotransmission that serotonin is capable of5–10. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, independent of its receptor-mediated actions. Atomic force microscopy shows that serotonin binding makes artificial lipid bilayers softer. It induces nucleation of liquid disordered domains inside the raft-like liquid-ordered domains in a ternary bilayer displaying phase separation. Solid-state NMR spectroscopy corroborates this data, revealing a rather homogeneous decrease in the order parameter of the lipid chains in the presence of serotonin. In the RN46A immortalized serotonergic neuronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, an action exerted even in the presence of both broad-spectrum serotonin receptor and transporter inhibitors. Similarly, it increases the binding and internalization of Islet Amyloid Polypeptide (IAPP) oligomers, suggesting a connection between serotonin, which is co-secreted with IAPP by pancreatic beta cells, and the cellular effects of IAPP. Our results uncover a hitherto unknown serotonin-bilayer interaction that can potentiate key cellular processes in a receptor-independent fashion. Therefore, some pathways of serotonergic action may escape potent pharmaceutical agents designed for serotonin transporters or receptors. Conversely, bio-orthogonal serotonin-mimetics may provide a new class of cell-membrane modulators.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biophysics↗

bioRxiv2020

Chronic chemogenetic activation of forebrain excitatory neurons in postnatal life evokes long-lasting changes in mood-related behavior

Early adversity is a key risk factor for the development of adult psychopathology, including anxiety, depression and schizophrenia. Rodent models of early adversity program persistent behavioral, molecular, metabolic, and neurophysiological changes. Perturbed signaling via forebrain Gq-coupled neurotransmitter receptors is a common feature across multiple models of early adversity. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke long-lasting mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of CamKII-positive forebrain excitatory neurons during postnatal life (P2-14) increased anxiety- and despair-like behavior, and evoked sensorimotor gating deficits in adulthood. In contrast, chronic chemogenetic hM3Dq DREADD activation of forebrain excitatory neurons in the juvenile or adult window did not evoke any mood-related behavioral alterations, highlighting the criticality of the postnatal temporal window. The enhanced anxiety-, despair- and schizophrenia-like behavioral changes evoked by chronic chemogenetic activation of forebrain excitatory neurons in postnatal life, was accompanied by an increased cortical and hippocampal metabolic rate of glutamatergic and GABAergic neurons in adulthood. Furthermore, animals with a history of postnatal hM3Dq activation exhibited a decline in the expression of activity-dependent and plasticity-associated markers within the hippocampus, along with perturbed hippocampal excitatory and inhibitory currents in adulthood. These results indicate that Gq signaling mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as metabolic and neurophysiological changes in forebrain glutamate and GABA systems, recapitulating specific aspects of the consequences of early adversity.

neuroscience↗

bioRxiv2019

Chemogenetic activation of excitatory neurons alters hippocampal neurotransmission in a dose-dependent manner

Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic tools are extensively used to manipulate neuronal activity in a cell-type specific manner. Whole-cell patch-clamp recordings indicate membrane depolarization, coupled with increased neuronal firing rate, following administration of the DREADD ligand, Clozapine-N-Oxide (CNO) to activate the Gq-coupled DREADD, hM3Dq. Although hM3Dq has been used to enhance neuronal firing in order to manipulate diverse behaviors, often within thirty minutes to an hour post-CNO administration, the physiological effects on excitatory neurotransmission remain poorly understood. We investigated the influence of CNO-mediated hM3Dq DREADD activation on distinct aspects of hippocampal excitatory neurotransmission at the Schaffer collateral-CA1 synapse in hippocampal slices derived from mice expressing hM3Dq in Ca2+/calmodulin dependent protein kinase (CamKII)-positive excitatory neurons. Our results indicate a clear dose-dependent effect on fEPSP slope, with no change noted at the lower dose of CNO (1 {micro}M) and a significant, long-term decline in fEPSP slope observed at higher doses (5-20 {micro}M). Further, we noted a robust theta burst stimulus (TBS) induced long-term potentiation (LTP) in the presence of the lower CNO (1 {micro}M) dose, which was significantly attenuated at the higher CNO (20 {micro}M) dose. Whole-cell patch clamp recording revealed both complex dose-dependent regulation of excitability, and spontaneous and evoked activity of CA1 pyramidal neurons in response to hM3Dq activation across CNO concentrations. Our data indicate that CNO-mediated activation of the hM3Dq DREADD results in dose-dependent regulation of excitatory hippocampal neurotransmission, and highlight the importance of careful interpretation of behavioral experiments involving chemogenetic manipulation.

neuroscience↗

bioRxiv2018

Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis

Mitochondria in neurons in addition to their primary role in bioenergetics also contribute to specialized functions including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1-PGC-1 axis, which is relevant to the neuroprotective action of 5-HT. 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial genes. This was accompanied by increased cellular ATP levels, basal and maximal respiration, as well as spare respiratory capacity. Mechanistically the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels, in a SIRT1 dependent manner. In cortical neurons, 5-HT enhanced expression of anti-oxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as a novel upstream regulator of mitochondrial biogenesis and function in cortical neurons, and implicate the mitochondrial effects of 5-HT in its neuroprotective action.

neuroscience↗