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Complementary Medicines
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1.
Cell Rep ; 31(2): 107495, 2020 04 14.
Article in English | MEDLINE | ID: mdl-32294447

ABSTRACT

Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, Tbr1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3ß inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD.


Subject(s)
Dendritic Spines/metabolism , T-Box Domain Proteins/metabolism , Wnt Signaling Pathway/physiology , Animals , Autism Spectrum Disorder/genetics , DNA-Binding Proteins/metabolism , Dendritic Spines/physiology , Female , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurogenesis/physiology , Neurons/metabolism , Neurons/physiology , Synapses/metabolism , T-Box Domain Proteins/genetics , T-Box Domain Proteins/physiology , Thalamus/metabolism , Wnt Signaling Pathway/genetics
2.
J Neurosci ; 38(10): 2569-2578, 2018 03 07.
Article in English | MEDLINE | ID: mdl-29437889

ABSTRACT

Behavioral tasks involving auditory cues activate inhibitory neurons within auditory cortex, leading to a reduction in the amplitude of auditory evoked response potentials (ERPs). One hypothesis is that this process, termed "task engagement," may enable context-dependent behaviors. Here we set out to determine (1) whether the medial prefrontal cortex (mPFC) plays a role in task engagement and (2) how task engagement relates to the context-dependent processing of auditory cues in male and female mice performing a decision-making task that can be guided by either auditory or visual cues. We found that, in addition to auditory ERP suppression, task engagement is associated with increased mPFC activity and an increase in theta band (4-7 Hz) synchronization between the mPFC and auditory cortex. Optogenetically inhibiting the mPFC eliminates the task engagement-induced auditory ERP suppression, while also preventing mice from switching between auditory and visual cue-based rules. However, mPFC inhibition, which eliminates task engagement-induced auditory ERP suppression, did not prevent mice from making decisions based on auditory cues. Furthermore, a more specific manipulation, selective disruption of mPFC outputs to the mediodorsal (MD) thalamus, is sufficient to prevent switching between auditory and visual rules but does not affect auditory ERPs. Based on these findings, we conclude that (1) the mPFC contributes to both task engagement and behavioral flexibility; (2) mPFC-MD projections are important for behavioral flexibility but not task engagement; and (3) task engagement, evidenced by the suppression of cortical responses to sensory input, is not required for sensory cue-guided decision making.SIGNIFICANCE STATEMENT When rodents perform choice-selection tasks based on sensory cues, neural responses to these cues are modulated compared with task-free conditions. Here we demonstrate that this phenomenon depends on the prefrontal cortex and thus represents a form of "top-down" regulation. However, we also show that this phenomenon is not critical for task performance, as rodents can make decisions based on specific sensory cues even when the task-dependent modulation of responses to those cues is abolished. Furthermore, disrupting one specific set of prefrontal outputs impairs rule switching but not the task-dependent modulation of sensory responses. These results show that the prefrontal cortex comprises multiple circuits that mediate dissociable functions related to behavioral flexibility and sensory processing.


Subject(s)
Behavior, Animal/physiology , Mediodorsal Thalamic Nucleus/physiology , Prefrontal Cortex/physiology , Psychomotor Performance/physiology , Acoustic Stimulation , Animals , Auditory Cortex/physiology , Cues , Decision Making/physiology , Electroencephalography , Evoked Potentials/physiology , Female , Male , Mice , Mice, Inbred C57BL , Nerve Net/physiology , Photic Stimulation , Theta Rhythm/physiology
3.
Neuron ; 93(2): 291-298, 2017 Jan 18.
Article in English | MEDLINE | ID: mdl-28041880

ABSTRACT

GABAergic interneurons play critical roles in seizures, but it remains unknown whether these vary across interneuron subtypes or evolve during a seizure. This uncertainty stems from the unpredictable timing of seizures in most models, which limits neuronal imaging or manipulations around the seizure onset. Here, we describe a mouse model for optogenetic seizure induction. Combining this with calcium imaging, we find that seizure onset rapidly recruits parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptitde (VIP)-expressing interneurons, whereas excitatory neurons are recruited several seconds later. Optogenetically inhibiting VIP interneurons consistently increased seizure threshold and reduced seizure duration. Inhibiting PV+ and SOM+ interneurons had mixed effects on seizure initiation but consistently reduced seizure duration. Thus, while their roles may evolve during seizures, PV+ and SOM+ interneurons ultimately help maintain ongoing seizures. These results show how an optogenetically induced seizure model can be leveraged to pinpoint a new target for seizure control: VIP interneurons. VIDEO ABSTRACT.


Subject(s)
Disease Models, Animal , GABAergic Neurons/physiology , Interneurons/physiology , Mice , Motor Cortex/physiopathology , Neural Inhibition , Optogenetics/methods , Seizures/physiopathology , Animals , Channelrhodopsins , Electroencephalography , GABAergic Neurons/metabolism , Interneurons/metabolism , Motor Cortex/metabolism , Parvalbumins/metabolism , Seizures/metabolism , Somatostatin/metabolism , Vasoactive Intestinal Peptide/metabolism
4.
J Neurosci ; 36(41): 10489-10495, 2016 10 12.
Article in English | MEDLINE | ID: mdl-27733600

ABSTRACT

γ oscillations, which can be identified by rhythmic electrical signals ∼30-100 Hz, consist of interactions between excitatory and inhibitory neurons that result in rhythmic inhibition capable of entraining firing within local cortical circuits. Many possible mechanisms have been described through which γ oscillations could act on cortical circuits to modulate their responses to input, alter their patterns of activity, and/or enhance the efficacy of their outputs onto downstream targets. Recently, several studies have observed changes in behavior after optogenetically manipulating neocortical γ oscillations. Now, future studies should determine whether these manipulations elicit physiological correlates associated with specific mechanisms through which γ oscillations are hypothesized to modulate cortical circuit function. There are numerous such mechanisms, so identifying which ones are actually engaged by optogenetic manipulations known to affect behavior would help flesh out exactly how γ oscillations contribute to cortical circuit function under normal and/or pathological conditions.


Subject(s)
Cerebral Cortex/physiology , Gamma Rhythm/physiology , Neural Pathways/physiology , Animals , Behavior , Humans , Neocortex/physiology , Optogenetics , Periodicity
5.
Proc Natl Acad Sci U S A ; 109(34): 13829-34, 2012 Aug 21.
Article in English | MEDLINE | ID: mdl-22753490

ABSTRACT

Inhibitory interneurons regulate the responses of cortical circuits. In auditory cortical areas, inhibition from these neurons narrows spectral tuning and shapes response dynamics. Acute disruptions of inhibition expand spectral receptive fields. However, the effects of long-term perturbations of inhibitory circuitry on auditory cortical responses are unknown. We ablated ~30% of dendrite-targeting cortical inhibitory interneurons after the critical period by studying mice with a conditional deletion of Dlx1. Following the loss of interneurons, baseline firing rates rose and tone-evoked responses became less sparse in auditory cortex. However, contrary to acute blockades of inhibition, the sizes of spectral receptive fields were reduced, demonstrating both higher thresholds and narrower bandwidths. Furthermore, long-latency responses at the edge of the receptive field were absent. On the basis of changes in response dynamics, the mechanism for the reduction in receptive field size appears to be a compensatory loss of cortico-cortically (CC) driven responses. Our findings suggest chronic conditions that feature changes in inhibitory circuitry are not likely to be well modeled by acute network manipulations, and compensation may be a critical component of chronic neuronal conditions.


Subject(s)
Acoustic Stimulation , Auditory Cortex/physiology , Homeodomain Proteins/genetics , Interneurons/physiology , Neural Inhibition/physiology , Neurons/physiology , Transcription Factors/genetics , Action Potentials/physiology , Animals , Dendrites/metabolism , Electroencephalography/methods , Female , Male , Mice , Mice, Knockout , Models, Genetic , Neurons/drug effects , Phenotype , Time Factors
6.
J Neurosci ; 26(16): 4247-55, 2006 Apr 19.
Article in English | MEDLINE | ID: mdl-16624945

ABSTRACT

Rhythmic inhibition entrains the firing of excitatory neurons during oscillations throughout the brain. Previous work has suggested that the strength and duration of inhibitory input determines the synchrony and period, respectively, of these oscillations. In particular, sleep spindles result from a cycle of events including rhythmic inhibition and rebound bursts in thalamocortical (TC) neurons, and slowing and strengthening this inhibitory input may transform spindles into spike-wave discharges characteristic of absence epilepsy. Here, we used dynamic clamp to inject TC neurons with spindle-like trains of IPSCs and studied how modest changes in the amplitude and/or duration of these IPSCs affected the responses of the TC neurons. Contrary to our expectations, we found that prolonging IPSCs accelerates postinhibitory rebound (PIR) in TC neurons, and that increasing either the amplitude or duration of IPSCs desynchronizes PIR activity in a population of TC cells. Tonic injection of hyperpolarizing or depolarizing current dramatically alters the timing and synchrony of PIR. These results demonstrate that rhythmic PIR activity is an emergent property of interactions between intrinsic and synaptic currents, not just a passive reflection of incoming synaptic inhibition.


Subject(s)
Action Potentials/physiology , Cerebral Cortex/physiology , Neurons/physiology , Synapses/physiology , Thalamus/physiology , Action Potentials/drug effects , Animals , Cerebral Cortex/drug effects , GABA-A Receptor Agonists , In Vitro Techniques , Mice , Mice, Mutant Strains , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neurons/drug effects , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/physiology , Synapses/drug effects , Thalamus/drug effects , Zolpidem
7.
J Neurosci ; 23(9): 3649-57, 2003 May 01.
Article in English | MEDLINE | ID: mdl-12736336

ABSTRACT

Networks of interconnected inhibitory neurons, such as the thalamic reticular nucleus (TRN), often regulate neural oscillations. Thalamic circuits generate sleep spindles and may contribute to some forms of generalized absence epilepsy, yet the exact role of inhibitory connections within the TRN remains controversial. Here, by using mutant mice in which the thalamic effects of the anti-absence drug clonazepam (CZP) are restricted to either relay or reticular nuclei, we show that the enhancement of intra-TRN inhibition is both necessary and sufficient for CZP to suppress evoked oscillations in thalamic slices. Extracellular and intracellular recordings show that CZP specifically suppresses spikes that occur during bursts of synchronous firing, and this suppression grows over the course of an oscillation, ultimately shortening that oscillation. These results not only identify a particular anatomical and molecular target for anti-absence drug design, but also elucidate a specific dynamic mechanism by which inhibitory networks control neural oscillations.


Subject(s)
Biological Clocks/physiology , Neurons/physiology , Receptors, GABA-A/metabolism , Thalamus/physiology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Biological Clocks/drug effects , Clonazepam/pharmacology , Electric Stimulation , GABA Modulators/pharmacology , In Vitro Techniques , Mice , Mice, Mutant Strains , Nerve Net/physiology , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neurons/drug effects , Neurons/metabolism , Protein Subunits/drug effects , Protein Subunits/genetics , Protein Subunits/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/drug effects , Receptors, GABA-A/genetics , Thalamic Nuclei/drug effects , Thalamic Nuclei/physiology , Thalamus/cytology , Thalamus/drug effects
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