Search

For the human brain to operate, populations of neurons across anatomical structures must coordinate their activity within milliseconds. To date, our understanding of such interactions has remained limited. We recorded directly from the hippocampus (HPC), posteromedial cortex (PMC), ventromedial/orbital prefrontal cortex (OFC), and the anterior nuclei of the thalamus (ANT) during two experiments of autobiographical memory processing that are known from decades of neuroimaging work to coactivate these regions. In 31 patients implanted with intracranial electrodes, we found that the presentation of memory retrieval cues elicited a significant increase of low frequency (LF < 6 Hz) activity followed by cross-regional phase coherence of this LF activity before select populations of neurons within each of the four regions increased high-frequency (HF > 70 Hz) activity. The power of HF activity was modulated by memory content, and its onset followed a specific temporal order of ANT→HPC/PMC→OFC. Further, we probed cross-regional causal effective interactions with repeated electrical pulses and found that HPC stimulations cause the greatest increase in LF-phase coherence across all regions, whereas the stimulation of any region caused the greatest LF-phase coherence between that particular region and ANT. These observations support the role of the ANT in gating, and the HPC in synchronizing, the activity of cortical midline structures when humans retrieve self-relevant memories of their past. Our findings offer a fresh perspective, with high temporal fidelity, about the dynamic signaling and underlying causal connections among distant regions when the brain is actively involved in retrieving self-referential memories from the past. [ABSTRACT FROM AUTHOR]

Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, retinoic acid induced 1 (RAI1), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural Rai1 deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in Rai1-deficient brains. Deletion of Rai1 from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting Rai1 from the Emx1Cre-lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability. [ABSTRACT FROM AUTHOR]

Neural inhibition within the thalamus is integral in shaping thalamocortical oscillatory activity. Fast, synaptic inhibition is primarily mediated by activation of heteropentameric [GABA.sub.A] receptor complexes. Here, we examined the synaptic physiology and network properties of mice lacking [GABA.sub.A] receptor [alpha]3, a subunit that in thalamus is uniquely expressed by inhibitory neurons of the reticular nucleus (nRT). Deletion of this subunit produced a powerful compensatory gain in inhibitory postsynaptic response in nRT neurons. Although, other forms of inhibitory and excitatory synaptic transmission in the circuit were unchanged, evoked thalamic oscillations were strongly dampened in [alpha]3 knockout mice. Furthermore, pharmacologically induced thalamocortical absence seizures displayed a reduction in length and power in [alpha]3 knockout mice. These studies highlight the role of GABAergic inhibitory strength within nRT in the maintenance of thalamic oscillations, and demonstrate that inhibitory intra-nRT synapses are a critical control point for regulating higher order thalamocortical network activity. benzodiazepine | epilepsy | inhibition | knockout

Networks of inhibitory neurons regulate synchrony during many physiological and pathological oscillations. To explore how these effects depend on cellular, network, and synaptic factors, we developed and validated a semisynthetic inhibitory network that approximates simultaneous activity in multiple neurons by using consecutive responses from single cells. We recorded from three types of neurons, each of which forms interconnected networks in vivo, but has unique intrinsic properties. In all three cell types, fast inhibitory coupling generated emergent gamma oscillations. By contrast, inhibitory coupling desynchronized slower, spindle-frequency responses specifically in thalamic reticular neurons. The emergent gamma-frequency synchronization was also specific to tonic input and did not occur during responses to phasic inputs. These results illustrate how particular features of inhibitory networks (e.g., cell or input type) contribute to their synchronizing or desynchronizing functions. They also demonstrate phenomena (emergent gamma oscillations) that occur robustly in multiple cell types and may thus be a generic feature of inhibitory networks throughout the brain. dynamic clamp | GABAA receptor | neocortex | synchrony | thalamus

Neuropeptide Y (NPY) is widely expressed throughout the nervous system and is known to reduce excitatory (but also inhibitory) synaptic transmission in many CNS areas, leading to the proposal that it is an endogenous antiepileptic agent. In the neocortex, where NPY is present in [gamma]-aminobutyric acid (GABA)ergic interneurons, its effects on inhibitory and excitatory synaptic activities have not been completely explored. Here we report that NPY application elicits a long-lasting decrease in evoked excitatory postsynaptic current amplitude and a delayed, long-lasting increase in the amplitude of evoked monosynaptic inhibitory postsynaptic current (IPSC) in layer V pyramidal neurons of rat neocortex. The novel, late, NPY-mediated increase of inhibitory synaptic transmission is caused by modulation of [Ca.sup.2+]-dependent GABA release onto pyramidal neurons, as it was accompanied by an increase in [Ca.sup.2+]-dependent miniature IPSC frequency. NPY decreased evoked monosynaptic IPSCs in GABAergic interneurons, indicating that this neuropeptide has differential effects on different neuronal subtypes in the neocortex. Each of these NPY actions would decrease excitability in cortical circuits, a result that has important implications for both physiological neocortical operations as well as pathophysiological epileptiform activities.

Detailed information regarding the contribution of individual [Gamma]-aminobutyric acid (GABA)-containing inhibitory neurons to the overall synaptic activity of single postsynaptic cells is essential to our understanding of fundamental elements of synaptic integration and operation of neuronal circuits. For example, GABA-containing cells in the thalamic reticular nucleus (nRt) provide major inhibitory innervation of thalamic relay nuclei that is critical to thalamocortical rhythm generation. To investigate the contribution of individual nRt neurons to the strength of this internuclear inhibition, we obtained whole-cell recordings of unitary inhibitory postsynaptic currents (IPSCs) evoked in ventrobasal thalamocortical (VB) neurons by stimulation of single nRt cells in rat thalamic slices, in conjunction with intracellular biocytin labeling. Two types of monosynaptic IPSCs could be distinguished. 'Weak' inhibitory connections were characterized by a significant number of postsynaptic failures in response to presynaptic nRt action potentials and relatively small IPSCs. In contrast, 'strong' inhibition was characterized by the absence of postsynaptic failures and significantly larger unitary IPSCs. By using miniature IPSC amplitudes to infer quantal size, we estimated that unitary IPSCs associated with weak inhibition resulted from activation of 1-3 release sites, whereas stronger inhibition would require simultaneous activation of 5-70 release sites. The inhibitory strengths were positively correlated with the density of axonal swellings of the presynaptic nRt neurons, an indicator that characterizes different nRt axonai arborization patterns. These results demonstrate that there is a heterogeneity of inhibitory interactions between nRt and VB neurons, and that variations in gross morphological features of axonal arbors in the central nervous system can be associated with significant differences in postsynaptic response characteristics.

Synchronized network responses in thalamus depend on phasic inhibition originating in the thalamic reticular nucleus (nRt) and are mediated by the neurotransmitter [Gamma]-aminobutyric acid (GABA). A suggested role for intra-nRt connectivity in inhibitory phasing remains controversial. Recently, functional GABA type B ([GABA.sub.B]) receptors were demonstrated on nRt cells, and the slow time course of the [GABA.sub.B] synaptic response seems ideally suited to deinactivate low-threshold calcium channels. This promotes burst firing, a characteristic feature of synchronized responses. Here we investigate [GABA.sub.B]-mediated rebound burst firing in thalamic cells. Whole-cell current-clamp recordings were obtained from nRt cells and somatosensory thalamocortical relay cells in rat brain slices. Synthetic [GABA.sub.B] inhibitory postsynaptic potentials, generated by a hybrid computer-neuron synapse (dynamic clamp), triggered rebound low-threshold calcium spikes in both cell types when peak inhibitory postsynaptic potential hyperpolarization was greater than -92 mV. The threshold inhibitory postsynaptic potential conductance for rebound burst generation was comparable in nRt (7 nS) and thalamocortical (5 nS) cells. However, burst onset in nRt (1 s) was considerably delayed compared with thalamocortical (0.6 s) cells. Thus, [GABA.sub.B] inhibitory postsynaptic potentials can elicit low-threshold calcium spikes in both relay and nRt neurons, but the resultant oscillation frequency would be faster for thalamocortical-nRt networks (3 Hz) than for nRt-nRt networks (1-2 Hz). We conclude, therefore, that fast (>2 Hz) [GABA.sub.B]-dependent thalamic oscillations are maintained primarily by reciprocal connections between excitatory and inhibitory cells. These findings further indicate that when oscillatory neural networks contain both recurrent and reciprocal inhibition, then distinct population frequencies may result when one or the other type of inhibition is favored.

CLC-2 is a voltage-gated chloride channel that is widely expressed in mammalian tissues. In the central nervous system, CLC-2 appears in neurons and glia. Studies to define how this channel contributes to normal and pathophysiological function in the central nervous system raise questions that remain unresolved, in part due to the absence of precise pharmacological tools for modulating CLC-2 activity. Herein, we describe the development and optimization of AK-42, a specific small-molecule inhibitor of CLC-2 with nanomolar potency (IC50 = 17 ± 1 nM). AK-42 displays unprecedented selectivity (>1,000-fold) over CLC-1, the closest CLC-2 homolog, and exhibits no off-target engagement against a panel of 61 common channels, receptors, and transporters expressed in brain tissue. Computational docking, validated by mutagenesis and kinetic studies, indicates that AK-42 binds to an extracellular vestibule above the channel pore. In electrophysiological recordings of mouse CA1 hippocampal pyramidal neurons, AK-42 acutely and reversibly inhibits CLC-2 currents; no effect on current is observed on brain slices taken from CLC-2 knockout mice. These results establish AK-42 as a powerful tool for investigating CLC-2 neurophysiology. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that diazepam-binding inhibitor (DBI) mediates an endogenous benzodiazepine-mimicking (endozepine) effect on synaptic inhibition in the thalamic reticular nucleus (nRT). Here we demonstrate that DBI peptide colocalizes with both astrocytic and neuronal markers in mouse nRT, and investigate the role of astrocytic function in endozepine modulation in this nucleus by testing the effects of the gliotoxin fluorocitrate (FC) on synaptic inhibition and endozepine signaling in the nRT using patch-clamp recordings. FC treatment reduced the effective inhibitory charge of GABAA receptor (GABAAR)-mediated spontaneous inhibitory postsynaptic currents in WT mice, indicating that astrocytes enhance GABAAR responses in the nRT. This effect was abolished by both a point mutation that inhibits classical benzodiazepine binding to GABAARs containing the α3 subunit (predominant in the nRT) and a chromosomal deletion that removes the Dbi gene. Thus, astrocytes are required for positive allosteric modulation via the α3 subunit benzodiazepine-binding site by DBI peptide family endozepines. Outside-out sniffer patches pulled from neurons in the adjacent ventrobasal nucleus, which does not contain endozepines, show a potentiated response to laser photostimulation of caged GABA when placed in the nRT. FC treatment blocked the nRT-dependent potentiation of this response, as did the benzodiazepine site antagonist flumazenil. When sniffer patches were placed in the ventrobasal nucleus, however, subsequent treatment with FC led to potentiation of the uncaged GABA response, suggesting nucleus-specific roles for thalamic astrocytes in regulating inhibition. Taken together, these results suggest that astrocytes are required for endozepine actions in the nRT, and as such can be positive modulators of synaptic inhibition. [ABSTRACT FROM AUTHOR]

The authors discuss the reemergence of the role of cable properties in the initiation of action potential. They state two distinct paths of the cable theory, such as longitudinal way along central conductor and transversely through membrane or cable sheating. They add that either lower passive load or greater sodium ions (Na+) influx will favor local initiation or increase depolarization according to cable theory.

The article discusses the role of neurons in controlling sleep-to-wake transition and highlights the role of peptides called Hypocretins (Herts) which is secreted by hypothalamic neurons known to promote wakefulness. It reports that the study provides functional evidence that locus coeruleus (LC) is the main downstream effector which mediates the effects of Hcrt to promote wakefulness during nonrapid eye movement (NREM) during the inactive period.

Focuses on evidence that shows reliability of propagation for neocortical pyramidal neurons. Signs of electrical activity in individual submicron branch points and axonal swellings; Characterization of neurons in the central nervous system by complex axonal arborization patterns.

Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, retinoic acid induced 1 ( RAI1 ), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural Rai1 deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in Rai1 -deficient brains. Deletion of Rai1 from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting Rai1 from the Emx1 Cre -lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability.

Initiating and regulating vertebrate reproduction requires pulsatile release of gonadotropin-releasing hormone (GnRH1) from the hypothalamus. Coordinated GnRH1 release, not simply elevated absolute levels, effects the release of pituitary gonadotropins that drive steroid production in the gonads. However, the mechanisms underlying synchronization of GnRH1 neurons are unknown. Control of synchronicity by gap junctions between GnRH1 neurons has been proposed but not previously found. We recorded simultaneously from pairs of transgenically labeled GnRH1 neurons in adult male Astatotilapia burtoni cichlid fish. We report that GnRH1 neurons are strongly and uniformly interconnected by electrical synapses that can drive spiking in connected cells and can be reversibly blocked by meclofenamic acid. Our results suggest that electrical synapses could promote coordinated spike firing in a cellular assemblage of GnRH1 neurons to produce the pulsatile output necessary for activation of the pituitary and reproduction.