Biology subjects

Mann, E. O.

Publications and source records attributed to Mann, E. O..

9 recordsLinked to original sources

bioRxiv2025

Calcium-permeable AMPAR in hippocampal parvalbumin-expressing interneurons protect against memory interference

Parvalbumin-expressing (PV+) interneurons exert exquisite control over spike output, and plasticity in these inhibitory circuits may be important for maintaining network stability in learning and memory. PV+ interneuron recruitment is primarily mediated by GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPAR), which support anti-Hebbian plasticity. However, the functional significance of CP-AMPAR-mediated plasticity remains unknown. Using a viral approach to artificially express the GluA2 subunit in hippocampal PV+ interneurons, we replaced CP-AMPAR with GluA2-containing receptors, and in doing so reduced synaptically-evoked Ca2+ transients and anti-Hebbian plasticity. Transfection of hippocampal PV+ interneurons with GluA2 resulted in delay-dependent spatial working memory deficits which increased across trials per session, and impaired reversal learning in the Morris water maze but not initial acquisition. Our data suggest that loss of CP-AMPAR-mediated plasticity in these cells leads to proactive interference, revealing a significant role for dynamic recruitment of PV+ interneurons in the segregation of memories and accurate memory retrieval. HighlightsO_LIViral expression of GluA2 in PV+ interneurons alters synaptic AMPA receptor profile C_LIO_LIGluA2 overexpression in PV+ cells reduces synaptic Ca2+ transients and plasticity C_LIO_LIUpregulating GluA2 in PV+ cells causes delay-dependent deficits in working memory C_LIO_LIAcquisition of reference memories is preserved, but reversal learning is impaired C_LI

neuroscience↗

bioRxiv2025

Enhanced mGluR1 function causes motor deficits and region-specific Purkinje cell dysfunction

Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited neurodegenerative disorders with no effective treatment. Aberrant signalling through the metabotropic glutamate receptor (mGluR1) has been implicated in several SCAs. However, whether disease is caused through decreased or increased mGluR1 signalling remains controversial. Here, we generate the first mouse model of enhanced mGluR1 function by introducing a gain-of-function mutation (p.Y792C) that causes SCA44 in the metabotropic glutamate receptor 1 (Grm1) gene. Grm1 mutant mice recapitulate key pathophysiological aspects of SCA, including progressive motor deficits, altered climbing fibre innervation and perturbed Purkinje cell spontaneous activity. We report that changes in synaptic innervation and intrinsic Purkinje cell activity upon overactive mGluR1 signalling manifest in a lobule- and disease-stage-specific manner. Our findings demonstrate that enhanced mGluR1 function is a direct and specific driver of Purkinje cell dysfunction and pathology and provide a mechanism for understanding the selective vulnerability of different Purkinje cell populations in SCA.

neuroscience↗

bioRxiv2024

An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour.

Cortical layer 6 (L6) neurons uniquely respond to orexin - a neuropeptide influencing arousal and emotion. We show that Drd1a-Cre+ neurons in the prefrontal cortex are selectively sensitive to orexin and regulate prefrontal network activation in vitro and in vivo. Chronically silencing these neurons impairs orexin-induced prefrontal activation and reduces anxiety-like behaviour, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.

neuroscience↗

bioRxiv2024

An axonal brake on striatal dopamine output by cholinergic interneurons

Depolarisation of distal axons is necessary for neurons to translate somatic action potentials into neurotransmitter release. Studies have shown that striatal cholinergic interneurons (ChIs) can directly drive ectopic action potentials in dopamine (DA) axons and trigger DA release. However, here we show that this action occurs within a broader context of axonal signal integration whereby activation of ChIs and depolarisation of DA axons by nicotinic receptors (nAChRs) limits the subsequent depolarisation and release of DA in response to ensuing activity. We demonstrate that activation of ChIs and nAChRs in ex vivo mouse striatum, even when it does not trigger DA release that is detectable by fast-scan cyclic voltammetry, limits DA release for [~]100 ms by depressing subsequent axonal depolarisation and calcium summation. This axonal brake on DA release is stronger in dorsal than ventral striatum, and is unrelated to DA depletion. In vivo, antagonism of nAChRs in dorsal striatum elevated extracellular DA levels and promoted conditioned place-preference, underscoring its physiological relevance. Our findings reveal that under physiological conditions in vivo, ChIs acting via nAChRs dynamically attenuate DA output driven by DA neuron activity, leading to a predominantly inverse relationship between ACh and DA signalling that varies continuously with ChI activity.

neuroscience↗

bioRxiv2023

Oscillatory-Quality of sleep spindles: from properties to function

Sleep spindles are traditionally defined as 10-15Hz thalamo-cortical oscillations typical of NREM sleep. While substantial heterogeneity in the appearance or spatio-temporal dynamics of spindle events is well recognised, the physiological relevance of the underlying fundamental property - the oscillatory strength - has not been studied. Here we introduce a novel metric called oscillatory Quality (o-Quality), which is derived by fitting an auto-regressive model to short segments of electrophysiological signals, recorded from the cortex in mice, to identify and calculate the damping of spindle oscillations. We find that the o-Quality of spindles varies markedly across cortical layers and regions and reflects the level of synchrony within and between cortical networks. Furthermore, the o-Quality of spindles varies as a function of sleep-wake history, determines the strength of coupling between spindles and slow waves, and influences the responsiveness to sensory stimulation during sleep. Thus, the o-Quality emerges as a metric that, for the first time, directly links the spatio-temporal dynamics of sleep spindles with their functional role.

neuroscience↗

bioRxiv2022

Neuronal-spiking-based closed-loop stimulationduring cortical ON and OFF states in freely moving mice

The slow oscillation (SO) is a central neuronal dynamic during sleep and is generated by alternating periods of high and low neuronal activity (ON and OFF states). Mounting evidence causally links the SO to sleeps functions, and it has recently become possible to manipulate the SO non-invasively and phase-specifically. These developments represent promising clinical avenues, but they also highlight the importance of improving our understanding of how ON/OFF states affect incoming stimuli and what role they play in neuronal plasticity. Most studies using closed-loop stimulation rely on the electroencephalogram (EEG) and local field potential (LFP) signals, which reflect neuronal ON and OFF states only indirectly. Here we develop an online detection algorithm based on spiking activity recorded from laminar arrays in mouse motor cortex. We find that online detection of ON and OFF states reflects specific phases of spontaneous LFP SO. Our neuronal-spiking-based closed-loop procedure offers a novel opportunity for testing the functional role of SO in sleep-related restorative processes and neural plasticity.

neuroscience↗

bioRxiv2020

Miro1-dependent Mitochondrial Dynamics in Parvalbumin Interneurons

The spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca2+-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in parvalbumin interneurons and how changes in mitochondrial trafficking could alter brain network activity. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization. These changes were accompanied by an increase in the ex vivo hippocampal {gamma}-oscillation (30 - 80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.

neuroscience↗

bioRxiv2020

The role of the hypothalamus in cortical arousaland sleep homeostasis

Sleep and wakefulness are not simple homogenous all-or-none states, but instead are characterized by rich dynamics of brain activity across many temporal and spatial scales. Rapid global state transitions between waking and sleeping are believed to be controlled by hypothalamic circuits, but the contribution of the hypothalamus to within-state changes of sleep and wake "intensity" remains largely unexplored. Here we show that stimulation of inhibitory neurons in the preoptic hypothalamus does not merely trigger awakening from sleep, but the resulting awake state is also characterized by increased cortical activity. This activation is associated with a faster build-up of sleep pressure, proportional to the arousal level. These findings show that hypothalamic systems thought to exclusively control global state switching, also regulate within-state "intensity", which we propose as a key intrinsic variable in shaping the architecture of sleep/wake states across the 24h day.

neuroscience↗

bioRxiv2018

Motor cortex can modulate somatosensory processing via cortico-thalamo-cortical pathway

The somatosensory and motor systems are intricately linked, providing several routes for the sensorimotor interactions necessary for haptic processing. Here, we used electrical and optogenetic stimulation to study the circuits that enable primary motor cortex (M1) to exert top-down modulation of whisker-evoked responses, at the levels of brain stem, thalamus and somatosensory cortex (S1). We find that activation of M1 drives somatosensory responsive cells at all levels, and that this excitation is followed by a period of tactile suppression, which gradually increases in strength along the ascending somatosensory pathway. Using optogenetic stimulation in the layer-specific Cre driver lines, we find that activation of layer VI cortico-thalamic neurons is sufficient to drive spiking in higher order thalamus, and that this is reliably followed by excitation of S1, suggesting a cross-modal cortico-thalamo-cortical pathway. Cortico-thalamic excitation predicts the degree of subsequent tactile suppression, consistent with a strong role for thalamic circuits in the expression of inhibitory sensorimotor interactions. These results provide evidence of a role for M1 in dynamic modulation of S1, largely under cortico-thalamic control.

neuroscience↗