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.

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.

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.

MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex.

Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome, an autism spectrum-associated disorder with a host of neurological and sensory symptoms, but the pathogenic mechanisms remain elusive. Neuronal circuits are shaped by experience during critical periods of heightened plasticity. The maturation of cortical GABA inhibitory circuitry, the parvalbumin(+) (PV(+)) fast-spiking interneurons in particular, is a key component that regulates the initiation and termination of the critical period. Using MeCP2-null mice, we examined experience-dependent development of neural circuits in the primary visual cortex. The functional maturation of parvalbumin interneurons was accelerated upon vision onset, as indicated by elevated GABA synthetic enzymes, vesicular GABA transporter, perineuronal nets, and enhanced GABA transmission among PV interneurons. These changes correlated with a precocious onset and closure of critical period and deficient binocular visual function in mature animals. Reduction of GAD67 expression rescued the precocious opening of the critical period, suggesting its major role in MECP2-mediated regulation of experience-driven circuit development. Our results identify molecular changes in a defined cortical cell type and link aberrant developmental trajectory to functional deficits in a model of neuropsychiatric disorder.

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.

Target-specific properties of thalamocortical synapses onto layer 4 of mouse primary visual cortex.

In primary sensory cortices, thalamocortical (TC) inputs can directly activate excitatory and inhibitory neurons. In vivo experiments in the main input layer (L4) of primary visual cortex (V1) have shown that excitatory and inhibitory neurons have different tuning properties. The different functional properties may arise from distinct intrinsic properties of L4 neurons, but could also depend on cell type-specific properties of the synaptic inputs from the lateral geniculate nucleus of the thalamus (LGN) onto L4 neurons. While anatomical studies identified LGN inputs onto both excitatory and inhibitory neurons in V1, their synaptic properties have not been investigated. Here we used an optogenetic approach to selectively activate LGN terminal fields in acute coronal slices containing V1, and recorded monosynaptic currents from excitatory and inhibitory neurons in L4. LGN afferents made monosynaptic connections with pyramidal (Pyr) and fast-spiking (FS) neurons. TC EPSCs on FS neurons were larger and showed steeper short-term depression in response to repetitive stimulation than those on Pyr neurons. LGN inputs onto Pyr and FS neurons also differed in postsynaptic receptor composition and organization of presynaptic release sites. Together, our results demonstrate that LGN input onto L4 neurons in mouse V1 have target-specific presynaptic and postsynaptic properties. Distinct mechanisms of activation of feedforward excitatory and inhibitory neurons in the main input layer of V1 are likely to endow neurons with different response properties to incoming visual stimuli.

Inhibitory plasticity dictates the sign of plasticity at excitatory synapses.

The broad connectivity of inhibitory interneurons and the capacity of inhibitory synapses to be plastic make them ideal regulators of the level of excitability of many neurons simultaneously. Whether inhibitory synaptic plasticity may also contribute to the selective regulation of single neurons and local microcircuits activity has not been investigated. Here we demonstrate that in rat primary visual cortex inhibitory synaptic plasticity is connection specific and depends on the activation of postsynaptic GABAB-Gi/o protein signaling. Through the activation of this intracellular signaling pathway, inhibitory plasticity can alter the state of a single postsynaptic neuron and directly affect the induction of plasticity at its glutamatergic inputs. This interaction is modulated by sensory experience. Our data demonstrate that in recurrent circuits, excitatory and inhibitory forms of synaptic plasticity are not integrated as independent events, but interact to cooperatively drive the activity-dependent rewiring of local microcircuits.

Layer-specific experience-dependent rewiring of thalamocortical circuits.

Thalamocortical circuits are central to sensory and cognitive processing. Recent work suggests that the thalamocortical inputs onto L4 and L6, the main input layers of neocortex, are activated differently by visual stimulation. Whether these differences depend on layer-specific organization of thalamocortical circuits; or on specific properties of synapses onto receiving neurons is unknown. Here we combined optogenetic stimulation of afferents from the visual thalamus and paired recording electrophysiology in L4 and L6 of rat primary visual cortex to determine the organization and plasticity of thalamocortical synapses. We show that thalamocortical inputs onto L4 and L6 differ in synaptic dynamics and sensitivity to visual drive. We also demonstrate that the two layers differ in the organization of thalamocortical and recurrent intracortical connectivity. In L4, a significantly larger proportion of excitatory neurons responded to light activation of thalamocortical terminal fields than in L6. The local microcircuit in L4 showed a higher degree of recurrent connectivity between excitatory neurons than the microcircuit in L6. In addition, L4 recurrently connected neurons were driven by thalamocortical inputs of similar magnitude indicating the presence of local subnetworks that may be activated by the same axonal projection. Finally, brief manipulation of visual drive reduced the amplitude of light-evoked thalamocortical synaptic currents selectively onto L4. These data are the first direct indication that thalamocortical circuits onto L4 and L6 support different aspects of cortical function through layer-specific synaptic organization and plasticity.

Emerging feed-forward inhibition allows the robust formation of direction selectivity in the developing ferret visual cortex.

The computation of direction selectivity requires that a cell respond to joint spatial and temporal characteristics of the stimulus that cannot be separated into independent components. Direction selectivity in ferret visual cortex is not present at the time of eye opening but instead develops in the days and weeks following eye opening in a process that requires visual experience with moving stimuli. Classic Hebbian or spike timing-dependent modification of excitatory feed-forward synaptic inputs is unable to produce direction-selective cells from unselective or weakly directionally biased initial conditions because inputs eventually grow so strong that they can independently drive cortical neurons, violating the joint spatial-temporal activation requirement. Furthermore, without some form of synaptic competition, cells cannot develop direction selectivity in response to training with bidirectional stimulation, as cells in ferret visual cortex do. We show that imposing a maximum lateral geniculate nucleus (LGN)-to-cortex synaptic weight allows neurons to develop direction-selective responses that maintain the requirement for joint spatial and temporal activation. We demonstrate that a novel form of inhibitory plasticity, postsynaptic activity-dependent long-term potentiation of inhibition (POSD-LTPi), which operates in the developing cortex at the time of eye opening, can provide synaptic competition and enables robust development of direction-selective receptive fields with unidirectional or bidirectional stimulation. We propose a general model of the development of spatiotemporal receptive fields that consists of two phases: an experience-independent establishment of initial biases, followed by an experience-dependent amplification or modification of these biases via correlation-based plasticity of excitatory inputs that compete against gradually increasing feed-forward inhibition.

Experience-dependent switch in sign and mechanisms for plasticity in layer 4 of primary visual cortex.

Neural circuits are extensively refined by sensory experience during postnatal development. How the maturation of recurrent cortical synapses may contribute to events regulating the postnatal refinement of neocortical microcircuits remains controversial. Here we show that, in the main input layer of rat primary visual cortex, layer 4 (L4), recurrent excitatory synapses are endowed with multiple, developmentally regulated mechanisms for induction and expression of excitatory synaptic plasticity. Maturation of L4 synapses and visual experience lead to a sharp switch in sign and mechanisms for plasticity at recurrent excitatory synapses in L4 at the onset of the critical period for visual cortical plasticity. The state of maturation of excitatory pyramidal neurons allows neurons to engage different mechanisms for plasticity in response to the same induction paradigm. Experience is determinant for the maturation of L4 synapses, as well as for the transition between forms of plasticity and the mechanisms they may engage. These results indicate a tight correlation between the effects of sensory drive and maturation on cortical neurons and provide a new set of cellular mechanisms engaged in the postnatal refinement of cortical circuits.

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.

Potentiation of cortical inhibition by visual deprivation.

The fine-tuning of circuits in sensory cortex requires sensory experience during an early critical period. Visual deprivation during the critical period has catastrophic effects on visual function, including loss of visual responsiveness to the deprived eye, reduced visual acuity, and loss of tuning to many stimulus characteristics. These changes occur faster than the remodelling of thalamocortical axons, but the intracortical plasticity mechanisms that underlie them are incompletely understood. Long-term depression of excitatory intracortical synapses has been proposed as a general candidate mechanism for the loss of cortical responsiveness after visual deprivation. Alternatively (or in addition), the decreased ability of the deprived eye to activate cortical neurons could be due to enhanced intracortical inhibition. Here we show that visual deprivation leaves excitatory connections in layer 4 (the primary input layer to cortex) unaffected, but markedly potentiates inhibitory feedback between fast-spiking basket cells (FS cells) and star pyramidal neurons (star pyramids). Further, a previously undescribed form of long-term potentiation of inhibition (LTPi) could be induced at synapses from FS cells to star pyramids, and was occluded by previous visual deprivation. These data suggest that potentiation of inhibition is a major cellular mechanism underlying the deprivation-induced degradation of visual function, and that this form of LTPi is important in fine-tuning cortical circuitry in response to visual experience.

Critical period for inhibitory plasticity in rodent binocular V1.

Postnatal cortical circuit development is characterized by windows of heightened plasticity that contribute to the acquisition of mature connectivity and function. What drives the transition between different critical plasticity windows is not known. Here we show that a switch in sign of inhibitory plasticity correlates with the reported transition between the precritical period (pre-CP) and the critical period (CP) for ocular dominance plasticity (ODP). In layer 4 of binocular visual cortex (V1b), depression of inhibitory synapses onto pyramidal neurons is induced when rats are monocularly deprived for 2 d at the end of the third postnatal week (pre-CP), whereas potentiation is induced if the monocular deprivation is started in the fourth postnatal week (CP). The magnitude of potentiation increases with deprivations started close to the peak of the CP for ODP. The direction of inhibitory plasticity depends on the differential manipulation of circuits activated by the two eyes. During development, these two forms of plasticity shift the balance between excitation and inhibition of the circuit in opposite directions, whereas the excitatory synaptic drive remains unaffected. Inhibitory plasticity is thus fundamental in modulating cortical circuit refinement and might be one of the mechanisms promoting ocular dominance shifts.

The many forms and functions of long term plasticity at GABAergic synapses.

On February 12th 1973, Bliss and Lomo submitted their findings on activity-dependent plasticity of glutamatergic synapses. After this groundbreaking discovery, long-term potentiation (LTP) and depression (LTD) gained center stage in the study of learning, memory, and experience-dependent refinement of neural circuits. While LTP and LTD are extensively studied and their relevance to brain function is widely accepted, new experimental and theoretical work recently demonstrates that brain development and function relies on additional forms of plasticity, some of which occur at nonglutamatergic synapses. The strength of GABAergic synapses is modulated by activity, and new functions for inhibitory synaptic plasticity are emerging. Together with excitatory neurons, inhibitory neurons shape the excitability and dynamic range of neural circuits. Thus, the understanding of inhibitory synaptic plasticity is crucial to fully comprehend the physiology of brain circuits. Here, I will review recent findings about plasticity at GABAergic synapses and discuss how it may contribute to circuit 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.

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.

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.

Multiple modes of network homeostasis in visual cortical layer 2/3.

Sensory experience is crucial for shaping the cortical microcircuit during development and is thought to modify network function through several forms of Hebbian and homeostatic plasticity. Where and when these different forms of plasticity are expressed at particular synapse types within cortical microcircuits, and how they interact, is poorly understood. Here we investigated how two different visual deprivation paradigms, lid suture (LS) and intraocular TTX, affect the local microcircuit within layer 2/3 of rat visual cortex during the classical critical period for visual system plasticity. Both forms of visual deprivation produced a compensatory increase in the spontaneous firing of layer 2/3 pyramidal neurons in acute slices derived from monocular visual cortex. TTX increased spontaneous activity through an increase in the excitation/inhibition (E/I) balance within layer 2/3. In contrast, LS decreased the E/I balance by strongly depressing excitatory transmission, and the homeostatic increase in spontaneous activity was instead achieved through an increase in the intrinsic excitability of layer 2/3 pyramidal neurons. The microcircuit in layer 2/3 can thus use different forms of homeostatic plasticity to compensate for the loss of visual drive, depending on the specific demands produced by visual experience. The existence of multiple, partially redundant forms of homeostatic plasticity may ensure that network compensation can be achieved in response to a wide range of sensory perturbations.

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.