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.

Altered Thalamocortical Signaling in a Mouse Model of Parkinson's Disease.

Activation of the primary motor cortex (M1) is important for the execution of skilled movements and motor learning, and its dysfunction contributes to the pathophysiology of Parkinson's disease (PD). A well-accepted idea in PD research, albeit not tested experimentally, is that the loss of midbrain dopamine leads to decreased activation of M1 by the motor thalamus. Here, we report that midbrain dopamine loss altered motor thalamus input in a laminar- and cell type-specific fashion and induced laminar-specific changes in intracortical synaptic transmission. Frequency-dependent changes in synaptic dynamics were also observed. Our results demonstrate that loss of midbrain dopaminergic neurons alters thalamocortical activation of M1 in both male and female mice, and provide novel insights into circuit mechanisms for motor cortex dysfunction in a mouse model of PD.SIGNIFICANCE STATEMENT Loss of midbrain dopamine neurons increases inhibition from the basal ganglia to the motor thalamus, suggesting that it may ultimately lead to reduced activation of primary motor cortex (M1). In contrast with this line of thinking, analysis of M1 activity in patients and animal models of Parkinson's disease report hyperactivation of this region. Our results are the first report that midbrain dopamine loss alters the input-output function of M1 through laminar and cell type specific effects. These findings support and expand on the idea that loss of midbrain dopamine reduces motor cortex activation and provide experimental evidence that reconciles reduced thalamocortical input with reports of altered activation of motor cortex in patients with Parkinson's disease.

Experience-dependent plasticity of gustatory insular cortex circuits and taste preferences.

Early experience with food influences taste preference in adulthood. How gustatory experience influences development of taste preferences and refinement of cortical circuits has not been investigated. Here, we exposed weanling mice to an array of taste solutions and determined the effects on the preference for sweet in adulthood. We demonstrate an experience-dependent shift in sucrose preference persisting several weeks following the termination of exposure. A shift in sucrose palatability, altered neural responsiveness to sucrose, and inhibitory synaptic plasticity in the gustatory portion of the insular cortex (GC) were also induced. The modulation of sweet preference occurred within a restricted developmental window, but restoration of the capacity for inhibitory plasticity in adult GC reactivated the sensitivity of sucrose preference to taste experience. Our results establish a fundamental link between gustatory experience, sweet preference, inhibitory plasticity, and cortical circuit function and highlight the importance of early life nutrition in setting taste preferences.

Reduced Dopamine Signaling Impacts Pyramidal Neuron Excitability in Mouse Motor Cortex.

Dopaminergic modulation is essential for the control of voluntary movement; however, the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined whether chronic depletion of dopaminergic input to the entire motor circuit, via a mouse model of Parkinson's disease, was sufficient to shift M1 neuron excitability. We show that D1 receptor (D1R) and D2R antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In contrast, chronic depletion of dopamine to the motor circuit with 6-hydroxydopamine induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mechanisms engaged are distinct depending on the duration and origin of the manipulation. Our study highlights the broad influence of dopamine on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function.

Women in Neuroscience: Four Women's Contributions to Science and Society.

There has been increased cognizance of gender inequity and the importance of an inclusive and diverse approach to scientific research in recent years. However, the innovative work of women scientists is still undervalued based on reports of fewer women in leadership positions, limited citations of research spearheaded by women, reduced federal grant awards, and lack of recognition. Women have been involved in trailblazing work that paved the way for contemporary scientific inquiry. The strides made in current neuroscience include contributions from women who deserve more recognition. In this review, we discuss the work of four women whose groundbreaking scientific work has made ineffaceable marks in the neuroscience field. These women are pioneers of research and innovators and, in addition, contribute to positive change that bolsters the academic community and society. This article celebrates these women scientists, their substantial impacts in neuroscience, and the positive influence of their work on advancing society and culture.

The ins and outs of inhibitory synaptic plasticity: Neuron types, molecular mechanisms and functional roles.

GABAergic interneurons are highly diverse, and their synaptic outputs express various forms of plasticity. Compelling evidence indicates that activity-dependent changes of inhibitory synaptic transmission play a significant role in regulating neural circuits critically involved in learning and memory and circuit refinement. Here, we provide an updated overview of inhibitory synaptic plasticity with a focus on the hippocampus and neocortex. To illustrate the diversity of inhibitory interneurons, we discuss the case of two highly divergent interneuron types, parvalbumin-expressing basket cells and neurogliaform cells, which support unique roles on circuit dynamics. We also present recent progress on the molecular mechanisms underlying long-term, activity-dependent plasticity of fast inhibitory transmission. Lastly, we discuss the role of inhibitory synaptic plasticity in neuronal circuits' function. The emerging picture is that inhibitory synaptic transmission in the CNS is extremely diverse, undergoes various mechanistically distinct forms of plasticity and contributes to a much more refined computational role than initially thought. Both the remarkable diversity of inhibitory interneurons and the various forms of plasticity expressed by GABAergic synapses provide an amazingly rich inhibitory repertoire that is central to a variety of complex neural circuit functions, including memory.

LTD at amygdalocortical synapses as a novel mechanism for hedonic learning.

A novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long-term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.

From Hiring to Firing: Activation of Inhibitory Neurons and Their Recruitment in Behavior.

The investigation of GABAergic inhibitory circuits has substantially expanded over the past few years. The development of new tools and technology has allowed investigators to classify many diverse groups of inhibitory neurons by several delineating factors: these include their connectivity motifs, expression of specific molecular markers, receptor diversity, and ultimately their role in brain function. Despite this progress, however, there is still limited understanding of how GABAergic neurons are recruited by their input and how their activity is modulated by behavioral states. This limitation is primarily due to the fact that studies of GABAergic inhibition are mainly geared toward determining how, once activated, inhibitory circuits regulate the activity of excitatory neurons. In this review article, we will outline recent work investigating the anatomical and physiological properties of inputs that activate cortical GABAergic neurons, and discuss how these inhibitory cells are differentially recruited during behavior.

Non-canonical Wnt signaling regulates neural stem cell quiescence during homeostasis and after demyelination.

Adult neural stem cells (NSCs) reside in a specialized microenvironment, the subventricular zone (SVZ), which provides them with unique signaling cues to control their basic properties and prevent their exhaustion. While the signaling mechanisms that regulate NSC lineage progression are well characterized, the molecular mechanisms that trigger the activation of quiescent NSCs during homeostasis and tissue repair are still unclear. Here, we uncovered that the NSC quiescent state is maintained by Rho-GTPase Cdc42, a downstream target of non-canonical Wnt signaling. Mechanistically, activation of Cdc42 induces expression of molecules involved in stem cell identity and anchorage to the niche. Strikingly, during a demyelination injury, downregulation of non-canonical Wnt-dependent Cdc42 activity is necessary to promote activation and lineage progression of quiescent NSCs, thereby initiating the process of tissue repair.

Versatility and Flexibility of Cortical Circuits.

Cortical circuits are known to be plastic and adaptable, as shown by an impressive body of evidence demonstrating the ability of cortical circuits to adapt to changes in environmental stimuli, development, learning, and insults. In this review, we will discuss some of the features of cortical circuits that are thought to facilitate cortical circuit versatility and flexibility. Throughout life, cortical circuits can be extensively shaped and refined by experience while preserving their overall organization, suggesting that mechanisms are in place to favor change but also to stabilize some aspects of the circuit. First, we will describe the basic organization and some of the common features of cortical circuits. We will then discuss how this underlying cortical structure provides a substrate for the experience- and learning-dependent processes that contribute to cortical flexibility.

Emerging Mechanisms Underlying Dynamics of GABAergic Synapses.

Inhibitory circuits are diverse, yet with a poorly understood cell biology. Functional characterization of distinct inhibitory neuron subtypes has not been sufficient to explain how GABAergic neurotransmission sculpts principal cell activity in a relevant fashion. Our Mini-Symposium brings together several emerging mechanisms that modulate GABAergic neurotransmission dynamically from either the presynaptic or the postsynaptic site. The first two talks discuss novel developmental and neuronal subtype-specific contributions to the excitatory/inhibitory balance and circuit maturation. The next three talks examine how interactions between cellular pathways, lateral diffusion of proteins between synapses, and chloride transporter function at excitatory and inhibitory synapses and facilitate inhibitory synapse adaptations. Finally, we address functional differences within GABAergic interneurons to highlight the importance of diverse, flexible, and versatile inputs that shape network function. Together, the selection of topics demonstrates how developmental and activity-dependent mechanisms coordinate inhibition in relation to the excitatory inputs and vice versa.

Rapid plasticity of visually evoked responses in rat monocular visual cortex.

Sensory cortical circuits are shaped by experience during sensitive periods in development. In the primary visual cortex (V1) altered visual experience results in changes in visual responsiveness of cortical neurons. The experience-dependent refinement of the circuit in V1 is thought to rely on competitive interactions between feedforward circuits driven by the two eyes. However, recent data have provided evidence for an additional role of cortico-cortical circuits in this process. Indeed, experience-dependent changes in intracortical circuits can be induced rapidly and may result in rapid-onset functional changes. Unilateral occlusion of vision rapidly alters visual responsiveness, synaptic strength and connectivity of local circuits in the binocular region of V1 (V1b), where the inputs from the two eyes converge. In the monocular region of rodent V1 (V1m), where feedforward inputs from the ipsilateral eye are virtually absent, visual deprivation induces rapid plasticity in local circuits; however, functional changes seem to occur only after long periods of deprivation. In V1m there is currently no evidence for functional changes occurring within a time window compatible with that of local circuit plasticity. Here, we probed the visual responsiveness of neurons in rat V1m and assessed the effect of one day unilateral eye lid suture on single neuron visual responses. We report a novel form of plasticity within V1m that occurs on a timescale consistent with the earliest known changes in synaptic strength. Our data provide new insights into how sensory experience can rapidly modulate neuronal responses, even in the absence of direct competition between feedforward thalamocortical inputs.

Layer-specific Developmental Changes in Excitation and Inhibition in Rat Primary Visual Cortex.

Cortical circuits are profoundly shaped by experience during postnatal development. The consequences of altered vision during the critical period for ocular dominance plasticity have been extensively studied in rodent primary visual cortex (V1). However, little is known about how eye opening, a naturally occurring event, influences the maturation of cortical microcircuits. Here we used a combination of slice electrophysiology and immunohistochemistry in rat V1 to ask whether manipulating the time of eye opening for 3 or 7 d affects cortical excitatory and inhibitory synaptic transmission onto excitatory neurons uniformly across layers or induces laminar-specific effects. We report that binocular delayed eye opening for 3 d showed similar reductions of excitatory and inhibitory synaptic transmission in layers 2/3, 4, and 5. Synaptic transmission recovered to age-matched control levels if the delay was prolonged to 7 d, suggesting that these changes were dependent on binocular delay duration. Conversely, laminar-specific and long-lasting effects were observed if eye opening was delayed unilaterally. Our data indicate that pyramidal neurons located in different cortical laminae have distinct sensitivity to altered sensory drive; our data also strongly suggest that experience plays a fundamental role in not only the maturation of synaptic transmission, but also its coordination across cortical layers.

Fifty shades of inhibition.

Inhibitory circuits are essential for brain function. Our understanding of their synaptic organization has advanced extensively with the identification and classification of an impressive variety of neuron groups, receptor types, and patterns of connectivity. However, the conceptual discussion regarding the role of in neural circuits still revolves around the idea that its primary role is to regulate circuit excitability. Here, I will focus on recent findings from cortical circuits and argue that inhibitory circuits are central to the integration of incoming inputs and can promote sophisticated fine-scale control of local circuits. I propose that inhibitory circuits should not be viewed so much as brakes on principal neurons activity, but as primary contributors to a variety of neural network functions.

Neurophysiology and Regulation of the Balance Between Excitation and Inhibition in Neocortical Circuits.

Brain function relies on the ability of neural networks to maintain stable levels of activity, while experiences sculpt them. In the neocortex, the balance between activity and stability relies on the coregulation of excitatory and inhibitory inputs onto principal neurons. Shifts of excitation or inhibition result in altered excitability impaired processing of incoming information. In many neurodevelopmental and neuropsychiatric disorders, the excitability of local circuits is altered, suggesting that their pathophysiology may involve shifts in synaptic excitation, inhibition, or both. Most studies focused on identifying the cellular and molecular mechanisms controlling network excitability to assess whether they may be altered in animal models of disease. The impact of changes in excitation/inhibition balance on local circuit and network computations is not clear. Here we report findings on the integration of excitatory and inhibitory inputs in healthy cortical circuits and discuss how shifts in excitation/inhibition balance may relate to pathological phenotypes.

Laminar- and Target-Specific Amygdalar Inputs in Rat Primary Gustatory Cortex.

The primary gustatory cortex (GC) receives projections from the basolateral nucleus of the amygdala (BLA). Behavioral and electrophysiological studies demonstrated that this projection is involved in encoding the hedonic value of taste and is a source of anticipatory activity in GC. Anatomically, this projection is largest in the agranular portion of GC; however, its synaptic targets and synaptic properties are currently unknown. In vivo electrophysiological recordings report conflicting evidence about BLA afferents either selectively activating excitatory neurons or driving a compound response consistent with the activation of inhibitory circuits. Here we demonstrate that BLA afferents directly activate excitatory neurons and two distinct populations of inhibitory neurons in both superficial and deep layers of rat GC. BLA afferents recruit different proportions of excitatory and inhibitory neurons and show distinct patterns of circuit activation in the superficial and deep layers of GC. These results provide the first circuit-level analysis of BLA inputs to a sensory area. Laminar- and target-specific differences of BLA inputs likely explain the complexity of amygdalocortical interactions during sensory processing. SIGNIFICANCE STATEMENT: Projections from the basolateral nucleus of the amygdala (BLA) to the cortex convey information about the emotional value and the expectation of a sensory stimulus. Although much work has been done to establish the behavioral role of BLA inputs to sensory cortices, very little is known about the circuit organization of BLA projections. Here we provide the first in-depth analysis of connectivity and synaptic properties of the BLA input to the gustatory cortex. We show that BLA afferents activate excitatory and inhibitory circuits in a layer-specific and pattern-specific manner. Our results provide important new information about how neural circuits establishing the hedonic value of sensory stimuli and driving anticipatory behaviors are organized at the synaptic level.

Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of Depressive-like Behaviors through Reduced Secretion of FGF2.

NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders.