Local origin of excitatory-inhibitory tuning equivalence in a cortical network.

The interplay between excitation and inhibition determines the fidelity of cortical representations. The receptive fields of excitatory neurons are often finely tuned to encoded features, but the principles governing the tuning of inhibitory neurons remain elusive. In this study, we recorded populations of neurons in the mouse postsubiculum (PoSub), where the majority of excitatory neurons are head-direction (HD) cells. We show that the tuning of fast-spiking (FS) cells, the largest class of cortical inhibitory neurons, was broad and frequently radially symmetrical. By decomposing tuning curves using the Fourier transform, we identified an equivalence in tuning between PoSub-FS and PoSub-HD cell populations. Furthermore, recordings, optogenetic manipulations of upstream thalamic populations and computational modeling provide evidence that the tuning of PoSub-FS cells has a local origin. These findings support the notion that the equivalence of neuronal tuning between excitatory and inhibitory cell populations is an intrinsic property of local cortical networks.

Neurotransmitter levels in the basal ganglia are associated with intracortical circuit activity of the primary motor cortex in healthy humans.

BACKGROUND: The basal ganglia are strongly connected to the primary motor cortex (M1) and play a crucial role in movement control. Interestingly, several disorders showing abnormal neurotransmitter levels in basal ganglia also present concomitant anomalies in intracortical function within M1. OBJECTIVE/HYPOTHESIS: The main aim of this study was to clarify the relationship between neurotransmitter content in the basal ganglia and intracortical function at M1 in healthy individuals. We hypothesized that neurotransmitter content of the basal ganglia would be significant predictors of M1 intracortical function. METHODS: We combined magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) to test this hypothesis in 20 healthy adults. An extensive TMS battery probing common measures of intracortical, and corticospinal excitability was administered, and GABA and glutamate-glutamine levels were assessed from voxels placed over the basal ganglia and the occipital cortex (control region). RESULTS: Regression models using metabolite concentration as predictor and TMS metrics as outcome measures showed that glutamate level in the basal ganglia significantly predicted short interval intracortical inhibition (SICI) and intracortical facilitation (ICF), while GABA content did not. No model using metabolite measures from the occipital control voxel was significant. CONCLUSIONS: Taken together, these results converge with those obtained in clinical populations and suggest that intracortical circuits in human M1 are associated with the neurotransmitter content of connected but distal subcortical structures crucial for motor function.

Excitatory-inhibitory modulation of transcranial focus ultrasound stimulation on human motor cortex.

AIMS: Transcranial focus ultrasound stimulation (tFUS) is a promising non-invasive neuromodulation technology. This study aimed to evaluate the modulatory effects of tFUS on human motor cortex (M1) excitability and explore the mechanism of neurotransmitter-related intracortical circuitry and plasticity. METHODS: Single pulse transcranial magnetic stimulation (TMS)-eliciting motor-evoked potentials (MEPs) were used to assessed M1 excitability in 10 subjects. Paired-pulse TMS was used to measure the effects of tFUS on GABA- and glutamate-related intracortical excitability and 1 H-MRS was used to assess the effects of repetitive tFUS on GABA and Glx (glutamine + glutamate) neurometabolic concentrations in the targeting region in nine subjects. RESULTS: The etFUS significantly increased M1 excitability, decreased short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI). The itFUS significantly suppressed M1 excitability, increased SICI, LICI, and decreased intracortical facilitation (ICF). Seven times of etFUS decreased the GABA concentration (6.32%), increased the Glx concentration (12.40%), and decreased the GABA/Glx ratio measured by MRS, while itFUS increased the GABA concentration (18.59%), decreased Glx concentration (0.35%), and significantly increased GABA/Glx ratio. CONCLUSION: The findings support that tFUS with different parameters can exert excitatory and inhibitory neuromodulatory effects on the human motor cortex. We provide novel insights that tFUS change cortical excitability and plasticity by regulating excitatory-inhibition balance related to the GABAergic and glutamatergic receptor function and neurotransmitter metabolic level.

Differences in Startle and Prepulse Inhibition in Contactin-associated Protein-like 2 Knock-out Rats are Associated with Sex-specific Alterations in Brainstem Neural Activity.

The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are the pontine reticular nucleus (PnC) and pedunculopontine tegmentum (PPTg), respectively. Multi-unit responses from the PnC and PPTg in vivo of the same rats revealed sex-specific effects of loss of CASPR2 expression on PnC activity, but no effects on PPTg activity. Female Cntnap2-/- rats showed considerably increased PnC firing rates compared with female wildtypes, whereas the difference between the genotypes was modest in male rats. In contrast, for both females and males we found meager differences between the genotypes for PPTg firing rates and inhibition of PnC firing rates, indicating that altered firing rates of these brainstem structures are not responsible for decreased PPI in Cntnap2-/- rats. We conclude that the auditory processing changes seen in Cntnap2-/- rats are associated with, but cannot be fully explained by, differences in PnC firing rates, and that a loss of function mutation in the Cntnap2 gene has differential effects depending on sex.

Acoustic startle and prepulse inhibition deficits in adult monkeys with neonatal lesions of the hippocampus, amygdala and orbital frontal cortex.

Sensory-motor gating, the process of filtering sensory stimuli to modulate motor responses, is impaired in many psychiatric diseases but especially schizophrenia. Sensory-motor gating assessed with the prepulse inhibition paradigm (PPI) measures startle in response to preceding acoustic stimuli. PPI studies in rodents have consistently found that neonatal hippocampal lesions impair sensory-motor gating in adult animals, but its applicability to primates has yet to be tested. The study examined acoustic startle responses and PPI in adult rhesus monkeys with neonatal lesions of the hippocampus (Neo-Hibo), amygdala (Neo-Aibo), and orbital frontal cortex areas 11 and 13 (Neo-Oasp) and with sham-operations (Neo-C). All monkeys were initially habituated to the startle apparatus and assayed for acoustic startle response curves. Subsequently, PPI was measured with the prepulse occurring at 60, 120, 240, 480, 1000 and 5000 msec prior to the pulse onset. No significant group differences in baseline startle were found. Compared to Neo-C monkeys, Neo-Hibo monkeys showed normal startle curves as well as normal PPI at short prepulse delays but prepulse facilitation (PPF) at longer prepulse intervals. Neo-Aibo monkeys displayed enhanced startle responses with only minor changes in PPI, whereas Neo-Oasp monkeys had severe dampening of startle responses and impaired PPI at shorter prepulse intervals. These results support prior evidence from rodent literature of the involvement of each of these areas in the development of the complex cortico-limbic circuit modulating sensory-motor gating and may shade light on the specific neural structures associated with deficits in PPI reported in neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, and post-traumatic disorders.

The recruitment of indirect waves within primary motor cortex during motor imagery: A directional transcranial magnetic stimulation study.

Motor imagery (MI) refers to the mental simulation of an action without overt movement. While numerous transcranial magnetic stimulation (TMS) studies provided evidence for a modulation of corticospinal excitability and intracortical inhibition during MI, the neural signature within the primary motor cortex is not clearly established. In the current study, we used directional TMS to probe the modulation of the excitability of early and late indirect waves (I-waves) generating pathways during MI. Corticospinal responses evoked by TMS with posterior-anterior (PA) and anterior-posterior (AP) current flow within the primary motor cortex evoke preferentially early and late I-waves, respectively. Seventeen participants were instructed to stay at rest or to imagine maximal isometric contractions of the right flexor carpi radialis. We demonstrated that the increase of corticospinal excitability during MI is greater with PA than AP orientation. By using paired-pulse stimulations, we confirmed that short-interval intracortical inhibition (SICI) increased during MI in comparison to rest with PA orientation, whereas we found that it decreased with AP orientation. Overall, these results indicate that the pathways recruited by PA and AP orientations that generate early and late I-waves are differentially modulated by MI.

Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABAB-mediated inhibition compared to controls and NF1 patients, and that GABAA-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

Computational model predicts the neural mechanisms of prepulse inhibition in Drosophila larvae.

Prepulse inhibition (PPI) is a behavioural phenomenon in which a preceding weaker stimulus suppresses the startle response to a subsequent stimulus. The effect of PPI has been found to be reduced in psychiatric patients and is a promising neurophysiological indicator of psychiatric disorders. Because the neural circuit of the startle response has been identified at the cellular level, investigating the mechanism underlying PPI in Drosophila melanogaster larvae through experiment-based mathematical modelling can provide valuable insights. We recently identified PPI in Drosophila larvae and found that PPI was reduced in larvae mutated with the Centaurin gamma 1A (CenG1A) gene, which may be associated with autism. In this study, we used numerical simulations to investigate the neural mechanisms underlying PPI in Drosophila larvae. We adjusted the parameters of a previously developed Drosophila larvae computational model and demonstrated that the model could reproduce several behaviours, including PPI. An analysis of the temporal changes in neuronal activity when PPI occurs using our neural circuit model suggested that the activity of specific neurons triggered by prepulses has a considerable effect on PPI. Furthermore, we validated our speculations on PPI reduction in CenG1A mutants with simulations.

Short-term arm immobilization modulates excitability of inhibitory circuits within, and between, primary motor cortices.

Previous research has suggested that short-term immobilization of the arm may be a low-cost, non-invasive strategy to enhance the capacity for long-term potentiation (LTP)-like plasticity in primary motor cortex (M1). Short-term immobilization reduces corticospinal excitability (CSE) in the contralateral M1, and interhemispheric inhibition (IHI) from ipsi- onto contralateral M1 is increased. However, it is unclear whether reduced CSE and increased IHI are associated with changes in intracortical inhibition, which has been shown to be important for regulating neuroplasticity in M1. The current study used transcranial magnetic stimulation to evaluate the effects of short-term (6 h) arm immobilization on CSE, IHI, and intracortical inhibition measured bilaterally in 43 neurotypical young adults (23 immobilized). We replicated previous findings demonstrating that immobilization decreased CSE in, and increased IHI onto, the immobilized hemisphere, but a significant change in intracortical inhibition was not observed at the group level. Across individuals, decreased CSE was associated with a decreased short-interval intracortical inhibition, an index of GABAA -ergic inhibition, within the immobilized hemisphere only in the immobilization group. Previous research has demonstrated that decreases in GABAA -ergic inhibition are necessary for the induction of LTP-like plasticity in M1; therefore, decreased intracortical inhibition after short-term arm immobilization may provide a novel mechanism to enhance the capacity for LTP-like plasticity within M1 and may be a potential target for strategies to augment plasticity capacity to enhance motor learning in health and disease.

Perceptual spatial position induces the attentional enhancement of prepulse inhibition and its neural mechanism.

Prepulse inhibition (PPI) is a sensorimotor gating process that reduces the startling response when a weaker sensory stimulus precedes a sudden startling stimulus. Perceptual spatial separation (PSS) between the prepulse and the background noise was found to enhance PPI compared to perceptual spatial co-location (PSC). However, little is known about the perceptual characteristics of prepulses in the PSS that induce more inhibition of the startling response and the associated neural mechanism. The dorsocentral striatum (DCS) was the convergence of spatial information from the cortical and thalamic circuits. Our study investigated whether the perceptual spatial position of prepulses induced spatial attentional modulation of PPI. In addition, whether the DCS was involved in spatial attentional modulation's neural circuits of PPI. In our study, the relative perceptual image positions of the prepulse and masker were controlled by the playback time difference between the two loudspeakers, i.e., PSS and PSC. The specific spatial attention of the prepulse was conditioned by foot shock. The results revealed that PPI was generally enhanced after fear conditioning/conditioning-control manipulation across all rats. Further enhancement of PPI in the PSS condition occurred only in the fear conditioning position, not in the conditioning-control position. We first found that PPI did not show specific spatial enhancement in the drug-blocking bilateral DCS rats with 2 mM kynurenic acid. These results demonstrated that the perceptual spatial position modulated the spatial attention of prepulse and improved PPI. DCS was involved in the attentional modulation neural circuits of PPI and processed spatial information of prepulse.

Strengthening the GABAergic System Through Neurofeedback Training Suppresses Implicit Motor Learning.

Gamma-aminobutyric acid (GABA) activity within the primary motor cortex (M1) is essential for motor learning in cortical plasticity, and a recent study has suggested that real-time neurofeedback training (NFT) can self-regulate GABA activity. Therefore, this study aimed to investigate the effect of GABA activity strengthening via NFT on subsequent motor learning. Thirty-six healthy participants were randomly assigned to either an NFT group or control group, which received sham feedback. GABA activity was assessed for short intracortical inhibition (SICI) within the right M1 using paired-pulse transcranial magnetic stimulation. During the NFT intervention period, the participants tried to modulate the size of a circle, which was altered according to the degree of SICI in the NFT group. However, the size was altered independently of the degree of SICI in the control group. We measured the reaction time before, after (online learning), and 24 h after (offline learning) the finger-tapping task. Results showed the strengthening of GABA activity induced by the NFT intervention, and the suppression of the online but not the offline learning. These findings suggest that prior GABA activity modulation may affect online motor learning.

Threshold Tracked Short-Interval Intracortical Inhibition More Closely Predicts the Cortical Response to Transcranial Magnetic Stimulation.

OBJECTIVES: Short-interval intracortical inhibition (SICI) is a paired-pulse transcranial magnetic stimulation (TMS) technique that is commonly used to quantify intracortical inhibitory tone in the primary motor cortex. Whereas conventional measures of SICI (C-SICI) quantify inhibition by the amplitude of the motor evoked potential (MEP), alternative measures involving threshold tracked SICI (TT-SICI) instead record the TMS intensity required to maintain a consistent MEP amplitude. Although both C-SICI and TT-SICI are thought to reflect inhibition mediated by γ-aminobutyric acid type A (GABAA) receptors, recent evidence suggests that the mechanisms involved with each measure may not be equivalent. This study aimed to use combined TMS-electroencephalography (TMS-EEG) to investigate the cortical mechanisms contributing to C-SICI and TT-SICI. MATERIALS AND METHODS: In 20 young adults (30.6 ± 8.1 years), C-SICI and TT-SICI were recorded with multiple conditioning intensities, using both posterior-to-anterior (PA) and anterior-to-posterior (AP) induced currents, and this was compared with the TMS-evoked EEG potential (TEP). RESULTS: We found no relationship between the magnitude of C-SICI and TT-SICI within each current direction. However, there was a positive relationship between the slope (derived from multiple conditioning intensities) of inhibition recorded with C-SICI and TT-SICI, but only with a PA current. Furthermore, irrespective of conditioning intensity or current direction, measures of C-SICI were unrelated to TEP amplitude. In contrast, TT-SICI was predicted by the P30 generated with AP stimulation. CONCLUSIONS: Our findings further demonstrate that C-SICI and TT-SICI likely reflect different facets of GABAA-mediated processes, with inhibition produced by TT-SICI appearing to align more closely with TMS-EEG measures of cortical excitability.

Towards an expanded neuroscientific understanding of social play.

Play has been recognized as a complex and diverse set of behaviors that has been difficult to define. Play can range from rough and tumble play among rats to a human child playing a computer game. Play has been understood to exist in multiple forms such as social, object, and locomotor (Burghardt, 2005). In this article we review the literatures on the neural basis of social play, on heart rate variability, on behavioral switching and set-shifting, on prepulse inhibition of the acoustic startle reflex, and on learning at the level of the basal ganglia. Each of these neuronal pathways, aside from heart rate variability, is rooted in the parafascicular nucleus of the thalamus, an important neural substrate for social play. We argue that social play optimally balances a number of opposing neural pathways by engaging systems involved in safety versus danger (heart rate variability), automatized reactions versus learned reactions to new stimuli (behavioral switching and set-shifting), and gating relevant versus less relevant stimuli (prepulse inhibition of the acoustic startle reflex). The idea that play, in addition to its role in interpersonal adaptation to social life, may have a central role in optimizing flexibility and creativity in individual response to novelty has been explored by previous authors (Huizinga, 1955; Spinka et al., 2001; Pellegrini et al., 2007; Pellis and Pellis, 2017). In this paper we explore the possible underlying neural basis for this function of play, having to do with balancing various neural networks, and in doing so propose an expanded understanding of the nature and function of social play.

Age-related decline in cortical inhibitory tone strengthens motor memory.

Ageing disrupts the finely tuned excitation/inhibition balance (E:I) across cortex via a natural decline in inhibitory tone (γ-amino butyric acid, GABA), causing functional decrements. However, in young adults, experimentally lowering GABA in sensorimotor cortex enhances a specific domain of sensorimotor function: adaptation memory. Here, we tested the hypothesis that as sensorimotor cortical GABA declines naturally with age, adaptation memory would increase, and the former would explain the latter. Results confirmed this prediction. To probe causality, we used brain stimulation to further lower sensorimotor cortical GABA during adaptation. Across individuals, how stimulation changed memory depended on sensorimotor cortical E:I. In those with low E:I, stimulation increased memory; in those with high E:I stimulation reduced memory. Thus, we identified a form of motor memory that is naturally strengthened by age, depends causally on sensorimotor cortex neurochemistry, and may be a potent target for motor skill preservation strategies in healthy ageing and neurorehabilitation.

Obesity-induced astrocyte dysfunction impairs heterosynaptic plasticity in the orbitofrontal cortex.

Overconsumption of highly palatable, energy-dense food is considered a key driver of the obesity pandemic. The orbitofrontal cortex (OFC) is critical for reward valuation of gustatory signals, yet how the OFC adapts to obesogenic diets is poorly understood. Here, we show that extended access to a cafeteria diet impairs astrocyte glutamate clearance, which leads to a heterosynaptic depression of GABA transmission onto pyramidal neurons of the OFC. This decrease in GABA tone is due to an increase in extrasynaptic glutamate, which acts via metabotropic glutamate receptors to liberate endocannabinoids. This impairs the induction of endocannabinoid-mediated long-term plasticity. The nutritional supplement, N-acetylcysteine rescues this cascade of synaptic impairments by restoring astrocytic glutamate transport. Together, our findings indicate that obesity targets astrocytes to disrupt the delicate balance between excitatory and inhibitory transmission in the OFC.

The relationship between cholinergic system brain structure and function in healthy adults and patients with mild cognitive impairment.

We assessed the structure-function relationship of the human cholinergic system and hypothesized that structural measures are associated with short-latency sensory afferent inhibition (SAI), an electrophysiological measure of central cholinergic signal transmission. Healthy volunteers (n = 36) and patients with mild cognitive impairment (MCI, n = 20) underwent median nerve SAI and 3T structural MRI to determine the volume of the basal forebrain and the thalamus. Patients with MCI had smaller basal forebrain (p < 0.001) or thalamus volumes (p < 0.001) than healthy volunteers. Healthy SAI responders (> 10% SAI) had more basal forebrain volume than non-responders (p = 0.004) or patients with MCI (p < 0.001). More basal forebrain volume was associated with stronger SAI in healthy volunteers (r = 0.33, p < 0.05) but not patients with MCI. There was no significant relationship between thalamus volumes and SAI. Basal forebrain volume is associated with cholinergic function (SAI) in healthy volunteers but not in MCI patients. The in-vivo investigation of the structure-function relationship could further our understanding of the human cholinergic system in patients with suspected or known cholinergic system degeneration.

Neurophysiological modulations in the (pre)motor-motor network underlying age-related increases in reaction time and the role of GABA levels - a bimodal TMS-MRS study.

It has been argued that age-related changes in the neurochemical and neurophysiological properties of the GABAergic system may underlie increases in reaction time (RT) in older adults. However, the role of GABA levels within the sensorimotor cortices (SMC) in mediating interhemispheric interactions (IHi) during the processing stage of a fast motor response, as well as how both properties explain interindividual differences in RT, are not yet fully understood. In this study, edited magnetic resonance spectroscopy (MRS) was combined with dual-site transcranial magnetic stimulation (dsTMS) for probing GABA+ levels in bilateral SMC and task-related neurophysiological modulations in corticospinal excitability (CSE), and primary motor cortex (M1)-M1 and dorsal premotor cortex (PMd)-M1 IHi, respectively. Both CSE and IHi were assessed during the preparatory and premotor period of a delayed choice RT task. Data were collected from 25 young (aged 18-33 years) and 28 older (aged 60-74 years) healthy adults. Our results demonstrated that older as compared to younger adults exhibited a reduced bilateral CSE suppression, as well as a reduced magnitude of long latency M1-M1 and PMd-M1 disinhibition during the preparatory period, irrespective of the direction of the IHi. Importantly, in older adults, the GABA+ levels in bilateral SMC partially accounted for task-related neurophysiological modulations as well as individual differences in RT. In contrast, in young adults, neither task-related neurophysiological modulations, nor individual differences in RT were associated with SMC GABA+ levels. In conclusion, this study contributes to a comprehensive initial understanding of how age-related differences in neurochemical properties and neurophysiological processes are related to increases in RT.

Neurophysiological correlates of residual inhibition in tinnitus: Hints for trait-like EEG power spectra.

OBJECTIVE: To investigate oscillatory brain activity changes following acoustic stimulation in tinnitus and whether these changes are associated with behavioral measures of tinnitus loudness. Moreover, differences in ongoing brain activity between individuals with and without residual inhibition (RI) are examined (responders vs. non-responders). METHODS: Three different types of noise stimuli were administered for acoustic stimulation in 45 tinnitus patients. Subjects resting state brain activity was recorded before and after stimulation via EEG alongside with subjective measurements of tinnitus loudness. RESULTS: Delta, theta and gamma band power increased, whereas alpha and beta power decreased from pre to post stimulation. Acoustic stimulation responders exhibited reduced gamma and a trend for enhanced alpha activity with the latter localized in the right inferior temporal gyrus. Post stimulation, individuals experiencing RI showed higher theta, alpha and beta power with a peak power difference in the alpha band localized in the right superior temporal gyrus. Neither correlations with behavioral tinnitus measures nor stimulus-specific changes in EEG activity were present. CONCLUSIONS: Our observations might be indicative of trait-specific forms of oscillatory signatures in different subsets of the tinnitus population related to acoustic tinnitus suppression. SIGNIFICANCE: Results and insights are not only useful to understand basic neural mechanisms behind RI but are also valuable for general neural models of tinnitus.

An inhibitory hippocampal-thalamic pathway modulates remote memory retrieval.

Memories are supported by distributed hippocampal-thalamic-cortical networks, but the brain regions that contribute to network activity may vary with memory age. This process of reorganization is referred to as systems consolidation, and previous studies have examined the relationship between the activation of different hippocampal, thalamic, and cortical brain regions and memory age at the time of recall. While the activation of some brain regions increases with memory age, other regions become less active. In mice, here we show that the active disengagement of one such brain region, the anterodorsal thalamic nucleus, is necessary for recall at remote time-points and, in addition, which projection(s) mediate such inhibition. Specifically, we identified a sparse inhibitory projection from CA3 to the anterodorsal thalamic nucleus that becomes more active during systems consolidation, such that it is necessary for contextual fear memory retrieval at remote, but not recent, time-points post-learning.

Diversity of Receptive Fields and Sideband Inhibition with Complex Thalamocortical and Intracortical Origin in L2/3 of Mouse Primary Auditory Cortex.

Receptive fields of primary auditory cortex (A1) neurons show excitatory neuronal frequency preference and diverse inhibitory sidebands. While the frequency preferences of excitatory neurons in local A1 areas can be heterogeneous, those of inhibitory neurons are more homogeneous. To date, the diversity and the origin of inhibitory sidebands in local neuronal populations and the relation between local cellular frequency preference and inhibitory sidebands are unknown. To reveal both excitatory and inhibitory subfields, we presented two-tone and pure tone stimuli while imaging excitatory neurons (Thy1) and two types of inhibitory neurons (parvalbumin and somatostatin) in L2/3 of mice A1. We classified neurons into six classes based on frequency response area (FRA) shapes and sideband inhibition depended both on FRA shapes and cell types. Sideband inhibition showed higher local heterogeneity than frequency tuning, suggesting that sideband inhibition originates from diverse sources of local and distant neurons. Two-tone interactions depended on neuron subclasses with excitatory neurons showing the most nonlinearity. Onset and offset neurons showed dissimilar spectral integration, suggesting differing circuits processing sound onset and offset. These results suggest that excitatory neurons integrate complex and nonuniform inhibitory input. Thalamocortical terminals also exhibited sideband inhibition, but with different properties from those of cortical neurons. Thus, some components of sideband inhibition are inherited from thalamocortical inputs and are further modified by converging intracortical circuits. The combined heterogeneity of frequency tuning and diverse sideband inhibition facilitates complex spectral shape encoding and allows for rapid and extensive plasticity.SIGNIFICANCE STATEMENT Sensory systems recognize and differentiate between different stimuli through selectivity for different features. Sideband inhibition serves as an important mechanism to sharpen stimulus selectivity, but its cortical mechanisms are not entirely resolved. We imaged pyramidal neurons and two common classes of interneurons suggested to mediate sideband inhibition (parvalbumin and somatostatin positive) in the auditory cortex and inferred their inhibitory sidebands. We observed a higher degree of variability in the inhibitory sideband than in the local frequency tuning, which cannot be predicted from the relative high homogeneity of responses by inhibitory interneurons. This suggests that cortical sideband inhibition is nonuniform and likely results from a complex interplay between existing functional inhibition in the feedforward input and cortical refinement.