Pawan bista - Academia.edu (original) (raw)

Papers by Pawan bista

SUMMARYWhether mouse visual cortex contains orderly feature maps is debated. The overlapping patt... more SUMMARYWhether mouse visual cortex contains orderly feature maps is debated. The overlapping pattern of geniculocortical (dLGN) inputs with M2 muscarinic acetylcholine receptor-rich patches in layer 1 (L1) suggests a non-random architecture. Here, we found that L1 inputs from the lateral posterior thalamus (LP) avoid patches and target interpatches. Channelrhodopsin-assisted mapping of EPSCs in L2/3 shows that the relative excitation of parvalbumin-expressing interneurons (PVs) and pyramidal neurons (PNs) by dLGN, LP and cortical feedback are distinct and depend on whether the neurons reside in clusters aligned with patches or interpatches. Paired recordings from PVs and PNs shows that unitary IPSCs are larger in interpatches than patches. The spatial clustering of inhibition is matched by dense clustering of PV-terminals in interpatches. The results show that the excitation/inhibition balance across V1 is organized into patch and interpatch subnetworks which receive distinct long-r...

Cerebral Cortex, 2019

Hyperpolarization-activated cation channels are involved, among other functions, in learning and ... more Hyperpolarization-activated cation channels are involved, among other functions, in learning and memory, control of synaptic transmission and epileptogenesis. The importance of the HCN1 and HCN2 isoforms for brain function has been demonstrated, while the role of HCN4, the third major neuronal HCN subunit, is not known. Here we show that HCN4 is essential for oscillatory activity in the thalamocortical (TC) network. HCN4 is selectively expressed in various thalamic nuclei, excluding the thalamic reticular nucleus. HCN4-deficient TC neurons revealed a massive reduction of I h and strongly reduced intrinsic burst firing, whereas the current was normal in cortical pyramidal neurons. In addition, evoked bursting in a thalamic slice preparation was strongly reduced in the mutant mice probes. HCN4-deficiency also significantly slowed down thalamic and cortical oscillations during active wakefulness. Taken together, these results establish that thalamic HCN4 channels are essential for the production of rhythmic intrathalamic oscillations and determine regular TC oscillatory activity during alert states.

eLife, 2016

Diverse features of sensory stimuli are selectively processed in distinct brain areas. The relati... more Diverse features of sensory stimuli are selectively processed in distinct brain areas. The relative recruitment of inhibitory and excitatory neurons within an area controls the gain of neurons for appropriate stimulus coding. We examined how such a balance of inhibition and excitation is differentially recruited across multiple levels of a cortical hierarchy by mapping the locations and strengths of synaptic inputs to pyramidal and parvalbumin (PV)-expressing neurons in feedforward and feedback pathways interconnecting primary (V1) and two higher visual areas. While interareal excitation was stronger in PV than in pyramidal neurons in all layer 2/3 pathways, we observed a gradual scaling down of the inhibition/excitation ratio from the most feedforward to the most feedback pathway. Our results indicate that interareal gain control depends on the hierarchical position of the source and the target, the direction of information flow through the network, and the laminar location of targ...

Neuron, 2015

Highlights d Patchy organization of geniculocortical and intracortical input to layer 1 of V1 d P... more Highlights d Patchy organization of geniculocortical and intracortical input to layer 1 of V1 d Patchy inputs to layer 1 overlap with patchy expression of M2 acetylcholine receptor d Distinct spatiotemporal sensitivities of neurons aligned with patches in layer 1 d Multiple patches contained within point image

The Journal of Physiology, 2014

During the behavioural states of sleep and wakefulness thalamocortical relay neurons fire action ... more During the behavioural states of sleep and wakefulness thalamocortical relay neurons fire action potentials in high frequency bursts or tonic sequences, respectively. r The modulation of specific K + channel types, termed TASK and TREK, allows these neurons to switch between the two modes of activity. r In this study we show that the signalling lipids phosphatidylinositol 4,5-bisphosphate (PIP 2) and diacylglycerol (DAG), which are components of their membrane environment, switch on and shut off TREK and TASK channels, respectively. r These channel modulations contribute to a better understanding of the molecular basis of the effects of neurotransmitters such as ACh which are released by the brainstem arousal system. r The present report introduces PIP 2 and DAG as new elements of signal transduction in the thalamus.

Pflügers Archiv - European Journal of Physiology, 2014

The role of two-pore-domain background K + (K 2P

Pflügers Archiv - European Journal of Physiology, 2012

Mutations in genes coding for Ca 2+ channels were found in patients with childhood absence epilep... more Mutations in genes coding for Ca 2+ channels were found in patients with childhood absence epilepsy (CAE) indicating a contribution of Ca 2+-dependent mechanisms to the generation of spike-wave discharges (SWD) in humans. Since the involvement of Ca 2+ signals remains unclear, the aim of the present study was to elucidate the function of a Ca 2+-dependent K + channel (BK Ca) under physiological conditions and in the pathophysiological state of CAE. The activation of BK Ca channels is dependent on both voltage and intracellular Ca 2+ concentrations. Moreover, these channels exhibit an outstandingly high level of regulatory heterogeneity that builds the basis for the influence of BK Ca channels on different aspects of neuronal activity. Here, we analyse the contribution of BK Ca channels to firing of thalamocortical relay neurons, and we test the hypothesis that BK Ca channel activity affects the phenotype of a genetic rat model of CAE. We found that the activation of the β 2-adrenergic receptor/protein kinase A pathway resulted in BK Ca channel inhibition. Furthermore, BK Ca channels affect the number of action potentials fired in a burst and produced spike frequency adaptation during tonic activity. The latter result was confirmed by a computer modelling approach. We demonstrate that the β 2-adrenergic inhibition of BK Ca channels prevents spike frequency adaptation and, thus, might significantly support the tonic firing mode of thalamocortical relay neurons. In addition, we show that BK Ca channel functioning differs in epileptic WAG/Rij and thereby likely contributes to highly synchronised, epileptic network activity.

Neurobiology of Disease, 2012

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels represent the molecular... more Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels represent the molecular substrate of the hyperpolarization-activated inward current (I h). Although these channels act as pacemakers for the generation of rhythmic activity in the thalamocortical network during sleep and epilepsy, their developmental profile in the thalamus is not yet fully understood. Here we combined electrophysiological, immunohistochemical, and mathematical modeling techniques to examine HCN gene expression and I h properties in thalamocortical relay (TC) neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in an epileptic (WAG/Rij) compared to a non-epileptic (ACI) rat strain. Recordings of TC neurons between postnatal day (P) 7 and P90 in both rat strains revealed that I h was characterized by higher current density, more hyperpolarized voltage dependence, faster activation kinetics, and reduced cAMP-sensitivity in epileptic animals. All four HCN channel isoforms (HCN1-4) were detected in dLGN, and quantitative analyses revealed a developmental increase of protein expression of HCN1, HCN2, and HCN4 but a decrease of HCN3. HCN1 was expressed at higher levels in WAG/Rij rats, a finding that was correlated with increased expression of the interacting proteins filamin A (FilA) and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Analysis of a simplified computer model of the thalamic network revealed that the alterations of I h found in WAG/Rij rats compensate each other in a way that leaves I h availability constant, an effect that ensures unaltered cellular burst activity and thalamic oscillations. These data indicate that during postnatal developmental the hyperpolarizing shift in voltage dependency (resulting in less current availability) is compensated by an increase in current density in WAG/Rij thereby possibly limiting the impact of I h on epileptogenesis. Because HCN3 is expressed higher in young versus older animals, HCN3 likely does not contribute to alterations in I h in older animals.

Brain Research, 2010

Cholinergic deafferentation of telencephalon is a major factor contributing to cognitive impairme... more Cholinergic deafferentation of telencephalon is a major factor contributing to cognitive impairment in Alzheimer's disease. There is evidence that the degeneration of cholinergic fibers which innervate the cortex and hippocampus is due to the development of neurofibrillary tangles in the perikarya of origin. Neurofibrillary tangle formation has been modeled in the transgenic pR5 mouse strain that overexpresses the longest human tau isoform together with the P301L mutation that has been previously identified in familial cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To test the suitability of the pR5 model as a model of Alzheimer's disease concerning the cholinergic innervation of the telencephalon, we determined the expression of the human tau transgene and the presence of neurofibrillary changes in the basal nucleus of Meynert, the septal nuclei and the diagonal band of Broca, sources of cholinergic innervation of the cerebral cortex and hippocampus. We found that the cholinergic neurons of these nuclei, despite widespread expression of the human tau transgene, neither expressed human tau nor displayed immunoreactivity with antibodies AT8 and AT180 which recognize hyperphosphorylated tau. Immunoreactivity for choline-acetyl transferase did not reveal significant differences between pR5 mice and non-transgenic littermates in the basal forebrain, cortex and hippocampus. However, in the amygdala dystrophic cholinergic neurites were observed which were not present in non-transgenic mice. Our data show that although pR5 mice develop neurofibrillary lesions, they do not model the degeneration of basal forebrain cholinergic neurons observed in Alzheimer's disease.

Pflügers Archiv - European Journal of Physiology, 2011

Modulation of the standing outward current (I SO) by muscarinic acetylcholine (ACh) receptor (MAC... more Modulation of the standing outward current (I SO) by muscarinic acetylcholine (ACh) receptor (MAChR) stimulation is fundamental for the state-dependent change in activity mode of thalamocortical relay (TC) neurons. Here, we probe the contribution of MAChR subtypes, G proteins, phospholipase C (PLC), and two pore domain K + (K 2P) channels to this signaling cascade. By the use of spadin and A293 as specific blockers, we identify TWIKrelated K + (TREK)-1 channel as new targets and confirm TWIK-related acid-sensitve K + (TASK)-1 channels as known effectors of muscarinic signaling in TC neurons. These findings were confirmed using a high affinity blocker of TASK-3 and TREK-1, namely, tetrahexylammonium chloride. It was found that the effect of muscarinic stimulation was inhibited by M 1 AChR-(pirenzepine, MT-7) and M 3 AChR-specific (4-DAMP) antagonists, phosphoinositide-specific PLCβ (PI-PLC) inhibitors (U73122, ET-18-OCH 3), but not the phosphatidylcholinespecific PLC (PC-PLC) blocker D609. By comparison, depleting guanosine-5′-triphosphate (GTP) in the intracellular milieu nearly completely abolished the effect of MAChR stimulation. The block of TASK and TREK channels was accompanied by a reduction of the muscarinic effect on I SO. Current-clamp recordings revealed a membrane depolarization following MAChR stimulation, which was sufficient to switch TC neurons from burst to tonic This article is published as part of the Special Issue on Sleep.

Medicines, 2019

Trigeminal neuropathic pain is a chronic pain condition caused by damage or inflammation of the t... more Trigeminal neuropathic pain is a chronic pain condition caused by damage or inflammation of the trigeminal nerve or its branches, with both peripheral and central nervous system dysfunction contributing to the disorder. Trigeminal pain conditions present with diagnostic and therapeutic challenges to healthcare providers and often require multiple therapeutic approaches for pain reduction. This review will provide the overview of pathophysiology in peripheral and central nociceptive circuits that are involved in neuropathic pain conditions involving the trigeminal nerve and the current therapeutics that are used to treat these disorders. Recent advances in treatment of trigeminal pain, including novel therapeutics that target ion channels and receptors, gene therapy and monoclonal antibodies that have shown great promise in preclinical studies and clinical trials will also be described.