Inhibitory Gating Research Articles

Auditory Sensory Gating: Effects of Noise.

Cortical auditory evoked potentials (CAEPs) indicate that noise degrades auditory neural encoding, causing decreased peak amplitude and increased peak latency. Different types of noise affect CAEP responses, with greater informational masking causing additional degradation. In noisy conditions, attention can improve target signals' neural encoding, reflected by an increased CAEP amplitude, which may be facilitated through various inhibitory mechanisms at both pre-attentive and attentive levels. While previous research has mainly focused on inhibition effects during attentive auditory processing in noise, the impact of noise on the neural response during the pre-attentive phase remains unclear. Therefore, this preliminary study aimed to assess the auditory gating response, reflective of the sensory inhibitory stage, to repeated vowel pairs presented in background noise. CAEPs were recorded via high-density EEG in fifteen normal-hearing adults in quiet and noise conditions with low and high informational masking. The difference between the average CAEP peak amplitude evoked by each vowel in the pair was compared across conditions. Scalp maps were generated to observe general cortical inhibitory networks in each condition. Significant gating occurred in quiet, while noise conditions resulted in a significantly decreased gating response. The gating function was significantly degraded in noise with less informational masking content, coinciding with a reduced activation of inhibitory gating networks. These findings illustrate the adverse effect of noise on pre-attentive inhibition related to speech perception.

Neonatal GABAergic transmission primes vestibular gating of output for adult spatial navigation

GABAergic interneurons are poised with the capacity to shape circuit output via inhibitory gating. How early in the development of medial vestibular nucleus (MVN) are GABAergic neurons recruited for feedforward shaping of outputs to higher centers for spatial navigation? The role of early GABAergic transmission in assembling vestibular circuits for spatial navigation was explored by neonatal perturbation. Immunohistochemistry and confocal imaging were utilized to reveal the expression of parvalbumin (PV)-expressing MVN neurons and their perineuronal nets. Whole-cell patch-clamp recording, coupled with optogenetics, was conducted in vitro to examine the synaptic function of MVN circuitry. Chemogenetic targeting strategy was also employed in vivo to manipulate neuronal activity during navigational tests. We found in rats a neonatal critical period before postnatal day (P) 8 in which competitive antagonization of GABAergic transmission in the MVN retarded maturation of inhibitory neurotransmission, as evidenced by deranged developmental trajectory for excitation/inhibition ratio and an extended period of critical period-like plasticity in GABAergic transmission. Despite increased number of PV-expressing GABAergic interneurons in the MVN, optogenetic-coupled patch-clamp recording indicated null-recruitment of these neurons in tuning outputs along the ascending vestibular pathway. Such perturbation not only offset output dynamics of ascending MVN output neurons, but was further accompanied by impaired vestibular-dependent navigation in adulthood. The same perturbations were however non-consequential when applied after P8. Results highlight neonatal GABAergic transmission as key to establishing feedforward output dynamics to higher brain centers for spatial cognition and navigation.

Inhibitory Gating of Thalamocortical Inputs onto Rat Gustatory Insular Cortex.

In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is related to decision-making. Inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc), dramatically reduces GC taste responses, consistent with the hypothesis that VPMpc-GC projections carry taste information. Recordings in awake rodents reported that taste-responsive neurons can be found across GC, without segregated spatial mapping, raising the possibility that projections from the taste thalamus may activate GC broadly. In addition, we have shown that cortical inhibition modulates the integration of thalamic and limbic inputs, revealing a potential role for GABA transmission in gating sensory information to GC. Despite this wealth of information at the system level, the synaptic organization of the VPMpc-GC circuit has not been investigated. Here, we used optogenetic activation of VPMpc afferents to GC in acute slice preparations from rats of both sexes to investigate the synaptic properties and organization of VPMpc afferents in GC and their modulation by cortical inhibition. We hypothesized that VPMpc-GC synapses are distributed across GC, but show laminar- and cell-specific properties, conferring computationally flexibility to how taste information is processed. We also found that VPMpc-GC synaptic responses are strongly modulated by the activity regimen of VPMpc afferents, as well as by cortical inhibition activating GABAA and GABAB receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing.SIGNIFICANCE STATEMENT We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared with primary thalamocortical synapses onto other sensory areas. Ventral posteromedial thalamic nucleus afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation; thus, they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Thalamocortical activation of GC is gated by cortical inhibition, providing local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses in GC highlight unique features of the thalamocortical circuit for taste.

Principal component analysis of auditory ERPs discriminates mild cognitive impairment and Alzheimer’s disease from normal aging

AbstractBackgroundSensory gating refers to an inhibitory mechanism of the brain that protects higher cortical centers from being flooded with repetitive, redundant sensory inputs. Sensory gating is modulated by cholinergic transmission, the deterioration of which is a prominent neurochemical feature of Alzheimer’s disease (AD), the most common form of dementia in the elderly. The study investigated whether alterations in inhibitory gating, assessed by event‐related potentials (ERPs) in response to repeated auditory stimuli, can discriminate AD and mild cognitive impairment (MCI) from normal aging.MethodEvent‐related electroencephalogram was recorded from 38 AD patients, 37 MCI patients, and 38 elderly cognitively normal control (NC) participants in a conditioning–testing paradigm. ERP waveforms, stimulus‐locked changes in power, and inter‐trial phase clustering (ITPC) were extracted and submitted to a covariance‐based principal component analysis (PCA) to yield data‐driven component measures.ResultNon‐parametric cluster‐based permutation tests revealed statistically significant differences for ERP waveforms in separating AD, for power in separating AD and MCI, and for ITPC in separating AD, MCI, and NC from the other two groups pooled together.ConclusionThe study confirms that alterations in auditory sensory gating can discriminate between AD, MCI, and normal aging. Auditory ERPs might serve as an objective, non‐invasive, and cost‐effective method for evaluating cognitive decline suggestive of AD and to monitor disease progression, therapeutic efficacy, or effects of novel drug candidates in clinical trials.

Pre-trial fronto-occipital electrophysiological connectivity affects perception–action integration in response inhibition

Inhibition of inappropriate behavior is relevant in many everyday situations. Nevertheless, the mechanisms that induce response inhibition based on sensory information and what influences these mechanisms are not entirely understood. We examined neurophysiological processes of perception–action integration in response inhibition and the impact of the pre-trial neurophysiological functional connectivity state in the theta and alpha band on these integration processes. The study was motivated by the Theory of Event Coding framework. Within the trial, fronto-medial theta band activity and occipital alpha band activity revealed an opposing interplay depending on the necessity of (re-)binding event files, i.e., the disintegration and recombination of stimulus–response associations, during response inhibition. When response inhibition required the reconfiguration of event files, this was associated with increased theta band activity but lower alpha band activity, and vice versa for the retrieval of event files. Notably, the most substantial impact of pre-trial connectivity on the within-trial event file binding effect (the difference between conditions that require reconfiguration and those that do not) during response inhibition occurred between fronto-medial areas and areas of the ventral stream in the theta frequency band. This suggests a preparatory top-down control of sensory areas before stimulus presentation. Increased pre-trial connectivity was associated with a decreased event file binding effect in the alpha frequency band and an increased event file binding effect in the theta frequency band during response inhibition. This implies an impact of the pre-trial functional connectivity state on inhibitory gating processes of relevant information and event file (re-)binding during response inhibition. The study shows how perception–action integration during response inhibition is affected by preceding transient neurophysiological connectivity states.

Auricular Transcutaneous Vagus Nerve Stimulation Diminishes Alpha-Band-Related Inhibitory Gating Processes During Conflict Monitoring in Frontal Cortices.

BackgroundPursuing goals is compromised when being confronted with interfering information. In such situations, conflict monitoring is important. Theoretical considerations on the neurobiology of response selection and control suggest that auricular transcutaneous vagus nerve stimulation (atVNS) should modulate conflict monitoring. However, the neurophysiological-functional neuroanatomical underpinnings are still not understood.MethodsAtVNS was applied in a randomized crossover study design (n = 45). During atVNS or sham stimulation, conflict monitoring was assessed using a Flanker task. EEG data were recorded and analyzed with focus on theta and alpha band activity. Beamforming was applied to examine functional neuroanatomical correlates of atVNS-induced EEG modulations. Moreover, temporal EEG signal decomposition was applied to examine different coding levels in alpha and theta band activity.ResultsAtVNS compromised conflict monitoring processes when it was applied at the second appointment in the crossover study design. On a neurophysiological level, atVNS exerted specific effects because only alpha-band activity was modulated. Alpha-band activity was lower in middle and superior prefrontal regions during atVNS stimulation and thus lower when there was also a decline in task performance. The same direction of alpha-band modulations was evident in fractions of the alpha-band activity coding stimulus-related processes, stimulus-response translation processes, and motor response–related processes.ConclusionsThe combination of prior task experience and atVNS compromises conflict monitoring processes. This is likely due to reduction of the alpha-band–associated inhibitory gating process on interfering information in frontal cortices. Future research should pay considerable attention to boundary conditions affecting the direction of atVNS effects.

Differential Activity-Dependent Increase in Synaptic Inhibition and Parvalbumin Interneuron Recruitment in Dentate Granule Cells and Semilunar Granule Cells.

Strong inhibitory synaptic gating of dentate gyrus granule cells (GCs), attributed largely to fast-spiking parvalbumin interneurons (PV-INs), is essential to maintain sparse network activity needed for dentate dependent behaviors. However, the contribution of PV-INs to basal and input-driven sustained synaptic inhibition in GCs and semilunar granule cells (SGCs), a sparse morphologically distinct dentate projection neuron subtype, is currently unknown. In studies conducted in hippocampal slices from mice, we find that although basal IPSCs are more frequent in SGCs and optical activation of PV-INs reliably elicited IPSCs in both GCs and SGCs, optical suppression of PV-INs failed to reduce IPSC frequency in either cell type. Amplitude and kinetics of IPSCs evoked by perforant path (PP) activation were not different between GCs and SGCs. However, the robust increase in sustained polysynaptic IPSCs elicited by paired afferent stimulation was lower in SGCs than in simultaneously recorded GCs. Optical suppression of PV-IN selectively reduced sustained IPSCs in SGCs but not in GCs. These results demonstrate that PV-INs, while contributing minimally to basal synaptic inhibition in both GCs and SGCs in slices, mediate sustained feedback inhibition selectively in SGCs. The temporally selective blunting of activity-driven sustained inhibitory gating of SGCs could support their preferential and persistent recruitment during behavioral tasks.SIGNIFICANCE STATEMENT Our study identifies that feedback inhibitory regulation of dentate semilunar granule cells (SGCs), a sparse and functionally distinct class of projection neurons, differs from that of the classical projection neurons, GCs. Notably, we demonstrate relatively lower activity-dependent increase in sustained feedback inhibitory synaptic inputs to SGCs when compared with GCs which would facilitate their persistent activity and preferential recruitment as part of memory ensembles. Since dentate GC activity levels during memory processing are heavily shaped by basal and feedback inhibition, the fundamental differences in basal and evoked sustained inhibition between SGCs and GCs characterized here provide a framework to reorganize current understanding of the dentate circuit processing.

Selective attention involves a feature-specific sequential release from inhibitory gating

Selective attention is a fundamental cognitive mechanism that allows our brain to preferentially process relevant sensory information, while filtering out distracting information. Attention is thought to flexibly gate the communication of irrelevant information through top-down alpha-rhythmic (8–12 Hz) functional connections, which influence early visual processing. However, the dynamic effects of top-down influence on downstream visual processing remain unknown. Here, we used electroencephalography to investigate local and network effects of selective attention while subjects attended to distinct features of identical stimuli. We found that attention-related changes in the functional brain network organization emerge shortly after stimulus onset, accompanied by an overall decrease of functional connectivity. Signatures of attentional selection were evident from a sequential release from alpha-band parietal gating in feature-selective areas. The directed connectivity paths and temporal evolution of this release from gating were consistent with the sensory effect of each feature, providing a neural basis for how visual processing quickly prioritizes relevant information in functionally specialized areas.

Sleep loss drives acetylcholine- and somatostatin interneuron–mediated gating of hippocampal activity to inhibit memory consolidation

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type-specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type-specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss-driven inhibitory gate on hippocampal information processing.

Inhibitory gating of coincidence-dependent sensory binding in secondary auditory cortex

Integration of multi-frequency sounds into a unified perceptual object is critical for recognizing syllables in speech. This “feature binding” relies on the precise synchrony of each component’s onset timing, but little is known regarding its neural correlates. We find that multi-frequency sounds prevalent in vocalizations, specifically harmonics, preferentially activate the mouse secondary auditory cortex (A2), whose response deteriorates with shifts in component onset timings. The temporal window for harmonics integration in A2 was broadened by inactivation of somatostatin-expressing interneurons (SOM cells), but not parvalbumin-expressing interneurons (PV cells). Importantly, A2 has functionally connected subnetworks of neurons preferentially encoding harmonic over inharmonic sounds. These subnetworks are stable across days and exist prior to experimental harmonics exposure, suggesting their formation during development. Furthermore, A2 inactivation impairs performance in a discrimination task for coincident harmonics. Together, we propose A2 as a locus for multi-frequency integration, which may form the circuit basis for vocal processing.

028 Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

Abstract Introduction Sleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. Methods We first measured pS6 throughout the hippocampus after learning (single trial contextual fear conditioning; CFC), and after subsequent sleep or sleep deprivation (SD). To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons or cholinergic inputs to hippocampus from the medial septum (MS) while mice slept in the hours following CFC. We also inhibited these neuronal populations to assess effects on memory consolidation. Results We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial CFC, but is reduced throughout the hippocampus after brief SD – a manipulation which disrupts contextual fear memory (CFM) consolidation. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. . We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons, while inhibition of Sst+ interneurons enhances memory consolidation. Similarly, pharmacogenetic activation of cholinergic input to hippocampus from the MS disrupted CFM. Inhibition of MS cholinergic neurons promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression among DG granule cells. Conclusion Our data suggest that state-dependent gating of DG activity during SD is mediated by cholinergic input. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss. Support (if any) R01-NS118440 to SJA from NINDS, DP2-MH104119 to SJA from the NIH Director’s Office, and a Human Frontiers Science Program Young Investigator Award

Seasonal plasticity in the adult somatosensory cortex

Seasonal cycles govern life on earth, from setting the time for the mating season to influencing migrations and governing physiological conditions like hibernation. The effect of such changing conditions on behavior is well-appreciated, but their impact on the brain remains virtually unknown. We investigate long-term seasonal changes in the mammalian brain, known as Dehnel's effect, where animals exhibit plasticity in body and brain sizes to counter metabolic demands in winter. We find large seasonal variation in cellular architecture and neuronal activity in the smallest terrestrial mammal, the Etruscan shrew, Suncus etruscus Their brain, and specifically their neocortex, shrinks in winter. Shrews are tactile hunters, and information from whiskers first reaches the somatosensory cortex layer 4, which exhibits a reduced width (-28%) in winter. Layer 4 width (+29%) and neuron number (+42%) increase the following summer. Activity patterns in the somatosensory cortex show a prominent reduction of touch-suppressed neurons in layer 4 (-55%), the most metabolically active layer. Loss of inhibitory gating occurs with a reduction in parvalbumin-positive interneurons, one of the most active neuronal subtypes and the main regulators of inhibition in layer 4. Thus, a reduction in neurons in layer 4 and particularly parvalbumin-positive interneurons may incur direct metabolic benefits. However, changes in cortical balance can also affect the threshold for detecting sensory stimuli and impact prey choice, as observed in wild shrews. Thus, seasonal neural adaptation can offer synergistic metabolic and behavioral benefits to the organism and offer insights on how neural systems show adaptive plasticity in response to ecological demands.

Tinnitus Update.

This article provides an update on tinnitus for audiologists and other clinicians who provide tinnitus-specific services. Tinnitus can be attributable to hearing loss, somatosensory system dysfunction, or auditory cortex dysfunction, with hearing loss being the most common cause and serious underlying pathologies being rare. Hearing loss does not always lead to tinnitus, and patients with tinnitus do not always suffer from hearing loss. The first scenario is explained by a so-called inhibitory gating mechanism, whereas the second assumes that all tinnitus sufferers have some degree of hearing impairment, which might not be detected in standard audiological examinations. The treatments should aim at symptomatic relief and management of associated distress. Current treatment options include pharmacotherapy, education, counseling, cognitive behavioral therapy, and sound therapy.

A possible role of the norepinephrine system during sequential cognitive flexibility – Evidence from EEG and pupil diameter data

Sequential cognitive flexibility is a major requirement for goal-directed behavior. Recent findings show that inhibitory control processes are crucial for sequential cognitive flexibility. These processes are indicated by the ‘backward inhibition (BI) effect’ which emerges when a mental representation that has recently been suppressed in favour of another task has to be re-activated. Alterations in the catecholaminergic neural transmission including the norepinephrine (NE) system have been shown to modulate inhibitory processes. However, a possible role of the NE system in sequential cognitive flexibility is elusive. The present study examines the relevance of the NE system for sequential cognitive flexibility by integrating pupil diameter data and electrophysiological (EEG) data applying signal decomposition techniques and source localization. We show that the BI effects modulated amplitudes in the P1/N1 time window, as well as in the N2 time window. Correlating this data with the pupil diameter data only revealed substantial correlations in the P1/N1 time window. Moreover, it is shown that regions in the right inferior frontal gyrus are activated during modulations in the P1 time window, in which correlations with the pupil diameter data were also evident. The results are interpreted that sequential cognitive flexibility modulates early inhibitory gating processes (P1) which are related to the suppression of task-irrelevant information in inferior frontal regions. These processes are likely modulated by the NE system.

P50 inhibitory sensory gating in schizophrenia: analysis of recent studies

IntroductionInhibitory sensory gating of the P50 cerebral evoked potential to paired auditory stimuli (S1, S2) is a widely used paradigm for the study of schizophrenia and related conditions. Its use to measure genetic, treatment, and developmental effects requires a metric with more stable properties than the simple ratio of the paired responses. MethodsThis study assessed the ratio P50S2μV/P50S1μV and P50S2μV co-varied for P50S1μV in all 27 independent published studies that compared schizophrenia patients with healthy controls from 2000 to 2019. The largest study from each research group was selected. The Colorado research group's studies were excluded to eliminate bias from the first report of the phenomenon. ResultsAcross the 27 studies encompassing 1179 schizophrenia patients and 1091 healthy controls, both P50S2μV co-varied for P50S1μV and P50S2μV/P50S1μV significantly separated the patients from the controls (both P < 0.0001). Effect size for P50S2μV co-varied for P50S1μV is d' = 1.23. The normal distribution of P50S2μV co-varied for P50S1μV detected influences of maternal inflammation and effects on behavior in a recent developmental study, an emerging use for the P50 inhibitory gating measure. P50S2μV/P50S1μV was not normally distributed. Results from two multi-site NIMH genetics collaborations also support the use of P50S2μV as a biomarker. ConclusionBoth methods detect an abnormality of cerebral inhibition in schizophrenia with high significance across multiple independent laboratories. The normal distribution of P50S2μV co-varied for P50S1μV makes it more suitable for studies of genetic, treatment, and other influences on the development and expression of inhibitory deficits in schizophrenia.

Correcting navigation deficits in the adult by targeting inhibitory gating in central vestibular circuits

Correcting navigation deficits in the adult by targeting inhibitory gating in central vestibular circuits

Extensive Inhibitory Gating of Viscerosensory Signals by a Sparse Network of Somatostatin Neurons.

Integration and modulation of primary afferent sensory information begins at the first terminating sites within the CNS, where central inhibitory circuits play an integral role. Viscerosensory information is conveyed to the nucleus of the solitary tract (NTS) where it initiates neuroendocrine, behavioral, and autonomic reflex responses that ensure optimal internal organ function. This excitatory input is modulated by diverse, local inhibitory interneurons, whose functions are not clearly understood. Here we show that, in male rats, 65% of somatostatin-expressing (SST) NTS neurons also express GAD67, supporting their likely role as inhibitory interneurons. Using whole-cell recordings of NTS neurons, from horizontal brainstem slices of male and female SST-yellow fluorescent protein (YFP) and SST-channelrhodopsin 2 (ChR2)-YFP mice, we quantified the impact of SST-NTS neurons on viscerosensory processing. Light-evoked excitatory photocurrents were reliably obtained from SST-ChR2-YFP neurons (n = 16) and the stimulation-response characteristics determined. Most SST neurons (57%) received direct input from solitary tract (ST) afferents, indicating that they form part of a feedforward circuit. All recorded SST-negative NTS neurons (n = 72) received SST-ChR2 input. ChR2-evoked PSCs were largely inhibitory and, in contrast to previous reports, were mediated by both GABA and glycine. When timed to coincide, the ChR2-activated SST input suppressed ST-evoked action potentials at second-order NTS neurons, demonstrating strong modulation of primary viscerosensory input. These data indicate that the SST inhibitory network innervates broadly within the NTS, with the potential to gate viscerosensory input to powerfully alter autonomic reflex function and other behaviors.SIGNIFICANCE STATEMENT Sensory afferent input is modulated according to state. For example the baroreflex is altered during a stress response or exercise, but the basic mechanisms underpinning this sensory modulation are not fully understood in any sensory system. Here we demonstrate that the neuronal processing of viscerosensory information begins with synaptic gating at the first central synapse with second-order neurons in the NTS. These data reveal that the somatostatin subclass of inhibitory interneurons are driven by visceral sensory input to play a major role in gating viscerosensory signals, placing them within a feedforward circuit within the NTS.

Translating striatal activity from brain slice to whole animal neurophysiology: A guide for neuroscience research integrating diverse levels of analysis.

An important goal of this review is highlighting research in neuroscience as examples of multilevel functional and anatomical analyses addressing basic science issues and applying results to the understanding of diverse disorders. The research of Dr. Michael Levine, a leader in neuroscience, exemplifies this approach by uncovering fundamental properties of basal ganglia function and translating these findings to clinical applications. The review focuses on neurophysiological research connecting results from in vitro and in vivo recordings. A second goal is to utilize these research connections to produce novel, accurate descriptions for corticostriatal processing involved in varied, complex functions. Medium spiny neurons in striatum act as integrators combining input with baseline activity creating motivational "events." Basic research on corticostriatal synapses is described and links developed to issues with clinical relevance such as inhibitory gating, self-injurious behavior, and relative reward valuation. Work is highlighted on dopamine-glutamate interactions. Individual medium spiny neurons express both D1 and D2 receptors and encode information in a bivalent manner depending upon the mix of receptors involved. Current work on neurophysiology of reward processing has taken advantage of these basic approaches at the cellular and molecular levels. Future directions in studying physiology of reward processing and action sequencing could profit by incorporating the divergent ways dopamine modulates incoming neurochemical signals. Primary investigators leading research teams should mirror Mike Levine's efforts in "climbing the mountain" of scientific inquiry by performing analyses at different levels of inquiry, integrating the findings, and building comprehensive answers to problems unsolvable without this bold approach.

Stress peptides sensitize fear circuitry to promote passive coping

Survival relies on optimizing behavioral responses through experience. Animals often react to acute stress by switching to passive behavioral responses when coping with environmental challenge. Despite recent advances in dissecting mammalian circuitry for Pavlovian fear, the neuronal basis underlying this form of non-Pavlovian anxiety-related behavioral plasticity remains poorly understood. Here, we report that aversive experience recruits the posterior paraventricular thalamus (PVT) and corticotropin-releasing hormone (CRH) and sensitizes a Pavlovian fear circuit to promote passive responding. Site-specific lesions and optogenetic manipulations reveal that PVT-to-central amygdala (CE) projections activate anxiogenic neuronal populations in the CE that release local CRH in response to acute stress. CRH potentiates basolateral (BLA)-CE connectivity and antagonizes inhibitory gating of CE output, a mechanism linked to Pavlovian fear, to facilitate the switch from active to passive behavior. Thus, PVT-amygdala fear circuitry uses inhibitory gating in the CE as a shared dynamic motif, but relies on different cellular mechanisms (postsynaptic long-term potentiation vs. presynaptic facilitation), to multiplex active/passive response bias in Pavlovian and non-Pavlovian behavioral plasticity. These results establish a framework promoting stress-induced passive responding, which might contribute to passive emotional coping seen in human fear- and anxiety-related disorders.

Differential modulation of the auditory steady state response and inhibitory gating by chloral hydrate anesthesia

Auditory steady state response (ASSR) and inhibitory gating (IG) are electrophysiological examinations commonly used to evaluate the sensory and cognitive functions of the brain. In some clinic examinations and animal experiments, general anesthesia is necessary to conduct electrophysiological recordings. However, the effects of anesthesia on ASSR and IG remain unclear. For this reason, we recorded local field potentials though electrodes implanted in different brain areas of rats: the auditory cortex (AC), hippocampus (HC), amygdala (AMY), and prefrontal cortex (PFC), and compared the characteristics of ASSR and IG under anesthetized and conscious conditions. We found that ASSR signals were the strongest in the AC, and decreased sequentially in the HP, AMY, and PFC. Chloral hydrate anesthesia significantly reduced the power and phase-locking of ASSR in the AC, HP, and AMY. In contrast, the extent of IG in the AC was weakest and it increased sequentially in the HP, AMY, and PFC. Anesthesia had less effect on the extent of IG. Our results suggest that ASSR and IG may originate from different neural circuits and that IG is more resistant to general anesthesia and therefore better suited to examining the functioning of non-auditory brain regions.