Biology subjects

KHAKH, B. S.

Publications and source records attributed to KHAKH, B. S..

4 recordsLinked to original sources

bioRxiv2026

NMDA receptor-dependent Hebbian plasticity refines hippocampal spatial representations during two-dimensional navigation learning

Hippocampal place cell activity represents an animals location in space; yet, how hippocampal neuronal population dynamics change with spatial learning and the mechanisms underlying these activity changes, which drive allocentric navigation to a learned goal, are poorly understood. To address these questions, we performed calcium imaging with a novel wire-free waterproof miniaturized microscope to image the activity of large populations of hippocampal CA1 neurons during spatial learning of a two-dimensional navigational task, the Morris water maze. We followed the same cells during learning and were able to directly examine how each neuron in the ensemble, and the ensemble as a whole, changes its response properties. We found that neuronal spatial selectivity increased and population decoding of spatial location improved as mice learned to navigate to the goal. Viral CRISPR knock out of Grin1 (encoding the essential GluN1 NMDA receptor subunit) in dorsal hippocampal neurons, dramatically reduced long-term potentiation in CA1. This manipulation also prevented the increase in spatial selectivity and improvement of population decoding with spatial learning and resulted in learning deficits in the Morris water maze. Together, our results show that dorsal hippocampus NMDAR-dependent synaptic plasticity is essential for the learning-dependent refinement of CA1 place selectivity and improvement in population decoding of space.

neuroscience↗

bioRxiv2020

Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia

Astrocytes are widely implicated in CNS diseases, but their contributions to disease related phenotypes remain incompletely explored. Anhedonia accompanies several neurological and psychiatric diseases, including major depressive disorder (MDD) and Alzheimers disease (AD), both of which are associated with neuroinflammation. In order to explore how neuroinflammation affects astrocytes, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocytic gene expression using a neuroinflammation mouse model that displayed anhedonia as a phenotype. In this model, anhedonia was reversed by the fast acting antidepressant ketamine. Astrocyte specific gene expression alterations included those related to immune cell signaling, intracellular Ca2+ signaling, cholesterol biosynthesis, and metabolic pathways. Such changes peaked when anhedonia was greatest, and reversed to normal when anhedonia subsided. However, region-specific molecular identities between PFC and VCX astrocytes were maintained throughout, implying that astrocyte identities do not converge during neuroinflammation. We also mapped anhedonia-related astrocyte and bulk tissue gene expression changes onto published PFC single cell RNA sequencing data, and compared them to MDD and AD post-mortem human tissue samples to identify shared mechanisms. Finally, we assessed how neuroinflammation affected mPFC neuronal properties and detected no alterations at a time point when there was strong astrocyte reactivity. Our data show that neuroinflammation can cause significant and reversible changes in astrocyte gene expression and mouse behaviour without obvious neurotoxicity or loss of essential homeostatic functions. Furthermore, gene expression signatures accompanying neuroinflammation reveal pathways shared with MDD and AD, which display neuroinflammation as a comorbidity in humans. Significance statementAstrocytes are widely implicated in brain diseases, but their contributions to disease-related phenotypes remain incompletely explored. To make inroads into this problem, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocyte gene expression using a peripherally induced neuroinflammation mouse model that produced anhedonia - a phenotype associated with several brain disorders. Neuroinflammation caused reversible changes in mouse behaviour and astrocyte-specific gene expression changes, some of which were related to human post mortem data for major depressive disorder (MDD) and Alzheimers disease (AD), but without any clear evidence of neurotoxicity in PFC of mice. The astrocyte molecular alterations accompanying neuroinflammation-induced anhedonia will be informative to explore diverse brain disorders and the effects of neuroinflammation on the CNS more broadly.

neuroscience↗

bioRxiv2020

Astrocytes amplify cerebral blood flow elevation to sustained cortical activation in the awake mouse

Brain requires increased local cerebral blood flow (CBF) for as long as necessary during neuronal activation to match O2 and glucose supply with demand - termed functional hyperemia. Ca2+ elevation in astrocytes can drive arteriole dilation to increase CBF, yet affirmative evidence for the necessity of astrocytes in functional hyperemia in vivo is lacking. In awake and active mice, we discovered that functional hyperemia is bimodal with a distinct early and late component whereby arteriole dilation progresses as sensory stimulation is sustained. Clamping astrocyte Ca2+ signaling in vivo by expressing a high-affinity plasma membrane Ca2+ ATPase (CalEx) reduces sustained but not brief sensory-evoked arteriole dilation. Reciprocally, elevating astrocyte free Ca2+ using chemogenetics selectively augments sustained but not brief hyperemia. Neither locomotion, arousal, nor changes in neuronal signaling account for the selective effect of astrocyte Ca2+ on the late phase of the CBF response. Antagonizing NMDA-receptors or epoxyeicosatrienoic acid production reduces only the late component of functional hyperemia, leaving brief increases in CBF to sensory stimulation intact. We propose that a fundamental role of astrocyte Ca2+ is to amplify functional hyperemia when neuronal activation is prolonged.

neuroscience↗

bioRxiv2020

A fast genetically encoded fluorescent sensor for faithful in vivo acetylcholine detection in mice, fish, worms and flies

Here we design and optimize a genetically encoded fluorescent indicator, iAChSnFR, for the ubiquitous neurotransmitter acetylcholine, based on a bacterial periplasmic binding protein. iAChSnFR shows large fluorescence changes, rapid rise and decay kinetics, and insensitivity to most cholinergic drugs. iAChSnFR revealed large transients in a variety of slice and in vivo preparations in mouse, fish, fly and worm. iAChSnFR will be useful for the study of acetylcholine in all animals.

neuroscience↗