Biology subjects

Brandalise, F.

Publications and source records attributed to Brandalise, F..

6 recordsLinked to original sources

bioRxiv2026

An endocannabinoid-nitric oxide signaling switch triggers reciprocal inhibitory-excitatory plasticity at dopamine neuron inputs following prenatal cannabinoid exposure

Dynamic regulation of midbrain dopamine neuron activity is necessary for diverse processes including motivation, novelty detection, reinforcement learning, and cognitive flexibility. By setting the strength of synaptic inputs to dopaminergic neurons, endocannabinoid signaling is essential for regulating dopaminergic activity. Prenatal exposure to {Delta}9-tetrahydrocannabinol (THC), the main psychoactive substance in cannabis, is known to induce abnormal dopaminergic activity and increased susceptibility to psychopathology. However, how prenatal cannabinoid exposure (PCE) affects endocannabinoid-mediated synaptic plasticity of dopamine neurons remains largely unknown. Here, we use a rat model of PCE to directly determine this. We found that endocannabinoid-mediated synaptic plasticity at excitatory synapses on dopamine neurons of the ventral tegmental area (VTA) was absent in PCE male rat offspring, where the presynaptic nanoscale architecture of excitatory afferents onto VTA dopamine neurons was reorganized to impair the control of type-1 cannabinoid receptors on glutamate release. We demonstrate that, in response to postsynaptic depolarization, PCE dopamine cells switch to nitric oxide (NO) rather than endocannabinoid signaling to induce opposing forms of synaptic plasticity at inhibitory and excitatory inputs. We disclosed a NO-dependent long-term potentiation of GABAA-receptor-mediated synaptic transmission, and a long-term depression of glutamatergic synapses requiring presynaptic activation of GABAB-receptors. These PCE-induced reciprocal forms of synaptic plasticity reshape the balance of excitatory and inhibitory control over dopamine neurons, potentially contributing to increased vulnerability to psychiatric disorders.

neuroscience↗

bioRxiv2026

Sleep deprivation impairs information processing via dysregulation of chloride homeostasis in the prefrontal cortex

Sleep deprivation (SD) impairs information processing through alterations of prefrontal cortex (PFC) function, yet the molecular underpinnings of this process remain poorly understood. We previously showed that SD disrupts sensorimotor gating by elevating prefrontal levels of the neurosteroid allopregnanolone (AP), a positive allosteric modulator of GABA-A receptors. Here we identify a complementary, mechanistically independent process whereby SD alters GABA-A currents in the PFC of mice and rats. SD reduced membrane expression of the chloride exporter KCC2, leading to intracellular chloride accumulation and a depolarizing shift in GABA-A receptor reversal potential that weakened GABAergic inhibition. Pharmacological normalization of chloride homeostasis with bumetanide fully rescued SD-induced deficits in sensorimotor gating and information encoding. SD also upregulated BDNF, and intra-PFC antagonism of its receptor TrkB restored KCC2 expression and normalized information processing, identifying BDNF-TrkB signaling as an upstream driver of chloride dysregulation. Notably, blocking AP synthesis rescued behavioral deficits without correcting chloride imbalance, confirming mechanistic independence. Finally, combined administration of AP and a KCC2 blocker produced information-processing deficits akin to those induced by SD. These findings identify TrkB-dependent disruption of prefrontal chloride homeostasis as a druggable mechanism underlying sleep loss-induced cognitive dysfunction.

animal behavior and cognition↗

bioRxiv2025

Neurogliaform cells mediate interhemispheric modulation of sensory-evoked activity in cortical pyramidal neurons

Integration of bilateral sensory inputs requires effective communication between brain hemispheres. This interhemispheric communication is essential for sensory perception and involves reciprocal connections between homotopic sensory areas. A key role in this process is attributed to interhemispheric inhibition which, owing to its long-lasting form, is posited to operate largely through neurogliaform cells (NGCs). However, direct evidence on the role of NGCs in interhemispheric inhibition is missing. Here we show that NGCs in the mouse barrel cortex (BC) are engaged by interhemispheric callosal projections to modulate pyramidal neuron (PN) activity and sensory perception. Using optogenetics, ex vivo whole-cell recordings, and in vivo calcium imaging, we found that layer 1 and layer 2/3 (L1-3) NGCs are strongly activated by the callosal and suppressed by the thalamocortical pathway, suggesting that NGCs encode ipsilateral rather than contralateral whisker stimuli. We also found that direct stimulation of L1-3 NGCs modulates whisker-evoked activity in L2/3 and L5b PNs, and increases the perceptual threshold in a whisker-deflection detection task. Furthermore, these effects were recapitulated by direct stimulation of callosal projections and deflection of the ipsilateral whiskers respectively, suggesting that the effect of the callosal pathway on sensory perception is mediated by NGCs. Our results not only prove that NGCs mediate interhemispheric inhibition, but also demonstrate their role in sensory perception via modulation of the main units involved in cortical input and output.

neuroscience↗

bioRxiv2023

Higher-order thalamocortical projections selectively control excitability via NMDAR and mGluRI-mediated mechanisms.

The apical dendrites of layer (L) 2/3 pyramidal neurons in the mouse somatosensory cortex integrate synaptic input from long-range projections. Among those, inputs from the higher-order thalamic posteromedial nucleus may facilitate sensory-evoked cortical activity, but it remains elusive how this role emerges. Here we show using ex vivo dendritic recordings that these projections provide dense synaptic input to broad tufted neurons residing predominantly in L2 and cooperate with other inputs to produce NMDA spikes. They have the unique capacity to block two-pore domain potassium leak channels via group 1 metabotropic glutamate receptor (mGluRI) signaling, which increases excitability. Slender tufted L2/3 neurons and other long-range projections fail to invoke these mechanisms. In vivo imaging of calcium signals confirms the presence of mGluRI-dependent modulation of feedback-mediated spiking in L2. Our results imply that higher-order thalamocortical projections regulate neuronal excitability in a cell type and input-selective manner through fast NMDAR and mGluRI-dependent mechanisms.

neuroscience↗

bioRxiv2022

Impaired dendritic spike generation in the Fragile X prefrontal cortex is due to loss of dendritic sodium channels

Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na+ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) PFC neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild type and Fmr1 knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild type. Analysis of voltage responses to simulated in vivo "noisy" current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared wild type. Patch clamp recordings revealed that the dendritic Na+ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that input-output transformation is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K+ and dendritic HCN-channel function is reduced in ET neurons, we suggest that the integration of information by PFC circuits is fundamentally altered in Fragile X syndrome. KEY POINTSO_LIDendritic spike threshold is depolarized in Layer 5 PFC neurons in FX mice C_LIO_LISimultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX ET neurons C_LIO_LIOutside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons C_LI

neuroscience↗

bioRxiv2017

Conditioning by Subthreshold Synaptic Input Changes the Characteristic Firing Pattern of CA3 Hippocampal Neurons

Unlike synaptic strength, intrinsic excitability is assumed to be a stable property of neurons. For example, learning of somatic conductances is generally not incorporated into computational models, and the discharge pattern of neurons in response to test stimuli is frequently used as a basis for phenotypic classification. However, it is increasingly evident that signal processing properties of neurons are more generally plastic on the timescale of minutes. Here we demonstrate that the intrinsic firing patterns of CA3 neurons of the rat hippocampus in vitro undergo rapid long-term plasticity in response to a few minutes of only subthreshold synaptic conditioning. This plasticity on the spike-timing could also be induced by intrasomatic injection of subthreshold depolarizing pulses and was blocked by kinase inhibitors, indicating that discharge dynamics are modulated locally. Cluster analysis of firing patterns before and after conditioning revealed systematic transitions towards adapting and intrinsic burst behaviours, irrespective of the patterns initially exhibited by the cells. We used a conductance-based model to decide appropriate pharmacological blockade, and found that the observed transitions are likely due to recruitment of calcium and M-type potassium conductances. We conclude that CA3 neurons adapt their conductance profile to the subthreshold activity of their input, so that their intrinsic firing pattern is not a static signature, but rather a reflection of their history of subthreshold activity. In this way, recurrent output from CA3 neurons may collectively shape the temporal dynamics of their embedding circuits.\n\nNew & NoteworthyDespite being widely conserved across the animal phyla, it is still a mystery why nerve cells present diverse discharge dynamics upon somatic step currents. Adding a new timing dimension to the intrinsic plasticity literature, here we show that CA3 neurons rapidly adapt through the space of known firing patterns in response to the subthreshold signals that they receive from their embedding circuit. This result implies that CA3 neurons collectively adjust their network processing to the temporal statistics of their circuit.

neuroscience↗