Cortical interneurons in autism.

The mechanistic underpinnings of autism remain a subject of debate and controversy. Why do individuals with autism share an overlapping set of atypical behaviors and symptoms, despite having different genetic and environmental risk factors? A major challenge in developing new therapies for autism has been the inability to identify convergent neural phenotypes that could explain the common set of symptoms that result in the diagnosis. Although no striking macroscopic neuropathological changes have been identified in autism, there is growing evidence that inhibitory interneurons (INs) play an important role in its neural basis. In this Review, we evaluate and interpret this evidence, focusing on recent findings showing reduced density and activity of the parvalbumin class of INs. We discuss the need for additional studies that investigate how genes and the environment interact to change the developmental trajectory of INs, permanently altering their numbers, connectivity and circuit engagement.

Kcns3 deficiency disrupts Parvalbumin neuron physiology in mouse prefrontal cortex: Implications for the pathophysiology of schizophrenia.

The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on the expression of multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in the neocortex of subjects with schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. Therefore, to assess the role of Kv9.3 subunits in PV neuron function, we combined gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient mice. Kcns3 mRNA levels were ~ 50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing. Moreover, Kcns3 deficiency impaired the recruitment of PVBC firing at gamma frequency by stimuli mimicking synaptic input observed during cortical UP states. Our data indicate that Kv9.3 subunits are critical for PVBC physiology and suggest that KCNS3 deficiency in schizophrenia could impair PV neuron firing, possibly contributing to deficits in cortical gamma oscillations in the illness.

Development of parvalbumin neurons and perineuronal nets in the visual cortex of normal and dark-exposed cats.

During development, the visual system maintains a high capacity for modification by expressing characteristics permissive for plasticity, enabling neural circuits to be refined by visual experience to achieve their mature form. This period is followed by the emergence of characteristics that stabilize the brain to consolidate for lifetime connections that were informed by experience. Attenuation of plasticity potential is thought to derive from an accumulation of plasticity-inhibiting characteristics that appear at ages beyond the peak of plasticity. Perineuronal nets (PNNs) are molecular aggregations that primarily surround fast-spiking inhibitory neurons called parvalbumin (PV) cells, which exhibit properties congruent with a plasticity inhibitor. In this study, we examined the development of PNNs and PV cells in the primary visual cortex of a highly visual mammal, and assessed the impact that 10 days of darkness had on both characteristics. Here, we show that labeling for PV expression emerges earlier and reaches adult levels sooner than PNNs. We also demonstrate that darkness, a condition known to enhance plasticity, significantly reduces the density of PNNs and the size of PV cell somata but does not alter the number of PV cells in the visual cortex. The darkness-induced reduction of PV cell size occurred irrespective of whether neurons were surrounded by a PNN, suggesting that PNNs have a restricted capacity to inhibit plasticity. Finally, we show that PV cells surrounded by a PNN were significantly larger than those without one, supporting the view that PNNs may mediate trophic support to the cells they surround.

Differential Short-Term Plasticity of PV and SST Neurons Accounts for Adaptation and Facilitation of Cortical Neurons to Auditory Tones.

Cortical responses to sensory stimuli are strongly modulated by temporal context. One of the best studied examples of such modulation is sensory adaptation. We first show that in response to repeated tones pyramidal (Pyr) neurons in male mouse auditory cortex (A1) exhibit facilitating and stable responses, in addition to adapting responses. To examine the potential mechanisms underlying these distinct temporal profiles, we developed a reduced spiking model of sensory cortical circuits that incorporated the signature short-term synaptic plasticity (STP) profiles of the inhibitory parvalbumin (PV) and somatostatin (SST) interneurons. The model accounted for all three temporal response profiles as the result of dynamic changes in excitatory/inhibitory balance produced by STP, primarily through shifts in the relative latency of Pyr and inhibitory neurons. Transition between the three response profiles was possible by changing the strength of the inhibitory PV→Pyr and SST→Pyr synapses. The model predicted that a unit's latency would be related to its temporal profile. Consistent with this prediction, the latency of stable units was significantly shorter than that of adapting and facilitating units. Furthermore, because of the history-dependence of STP the model generated a paradoxical prediction: that inactivation of inhibitory neurons during one tone would decrease the response of A1 neurons to a subsequent tone. Indeed, we observed that optogenetic inactivation of PV neurons during one tone counterintuitively decreased the spiking of Pyr neurons to a subsequent tone 400 ms later. These results provide evidence that STP is critical to temporal context-dependent responses in the sensory cortex.SIGNIFICANCE STATEMENT Our perception of speech and music depends strongly on temporal context, i.e., the significance of a stimulus depends on the preceding stimuli. Complementary neural mechanisms are needed to sometimes ignore repetitive stimuli (e.g., the tic of a clock) or detect meaningful repetition (e.g., consecutive tones in Morse code). We modeled a neural circuit that accounts for diverse experimentally-observed response profiles in auditory cortex (A1) neurons, based on known forms of short-term synaptic plasticity (STP). Whether the simulated circuit reduced, maintained, or enhanced its response to repeated tones depended on the relative dominance of two different types of inhibitory cells. The model made novel predictions that were experimentally validated. Results define an important role for STP in temporal context-dependent perception.

Serial Prefrontal Pathways Are Positioned to Balance Cognition and Emotion in Primates.

The delicate balance among primate prefrontal networks is necessary for homeostasis and behavioral flexibility. Dorsolateral prefrontal cortex (dlPFC) is associated with cognition, while the most ventromedial subgenual cingulate area 25 (A25) is associated with emotion and emotional expression. Yet A25 is weakly connected with dlPFC, and it is unknown how the two regions communicate. In rhesus monkeys of both sexes, we investigated how these functionally distinct areas may interact through pregenual anterior cingulate area 32 (A32), which is strongly connected with both. We found that dlPFC innervated the deep layers of A32, while A32 innervated all layers of A25, mostly targeting spines of excitatory neurons. Approximately 20% of A32 terminations formed synapses on inhibitory neurons in A25, notably the powerful parvalbumin inhibitory neurons in the deep layers, and the disinhibitory calretinin neurons in the superficial layers. By innervating distinct inhibitory microenvironments in laminar compartments, A32 is positioned to tune activity in columns of A25. The circuitry of the sequential pathway indicates that when dlPFC is engaged, A32 can dampen A25 output through the parvalbumin inhibitory microsystem in the deep layers of A25. A32 thus may flexibly recruit or reduce activity in A25 to maintain emotional equilibrium, a process that is disrupted in depression. Moreover, pyramidal neurons in A25 had a heightened density of NMDARs, which are the targets of novel rapid-acting antidepressants. Pharmacologic antagonism of NMDARs in patients with depression may reduce excitability in A25, mimicking the effects of the neurotypical serial pathway identified here.SIGNIFICANCE STATEMENT The anterior cingulate is a critical hub in prefrontal networks through connections with functionally distinct areas. Dorsolateral and polar prefrontal areas that are associated with complex cognition are connected with the anterior cingulate in a pattern that allows them to indirectly control downstream activity from the anterior cingulate to the subgenual cingulate, which is associated with heightened activity and negative affect in depression. This set of pathways provides a circuit mechanism for emotional regulation, with the anterior cingulate playing a balancing role for integration of cognitive and emotional processes. Disruption of these pathways may perturb network function and the ability to regulate cognitive and affective processes based on context.

Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans.

Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

Whole-Brain Map of Long-Range Monosynaptic Inputs to Different Cell Types in the Amygdala of the Mouse.

The amygdala, which is involved in various behaviors and emotions, is reported to connect with the whole brain. However, the long-range inputs of distinct cell types have not yet been defined. Here, we used a retrograde trans-synaptic rabies virus to generate a whole-brain map of inputs to the main cell types in the mouse amygdala. We identified 37 individual regions that projected to neurons expressing vesicular glutamate transporter 2, 78 regions to parvalbumin-expressing neurons, 104 regions to neurons expressing protein kinase C-δ, and 89 regions to somatostatin-expressing neurons. The amygdala received massive projections from the isocortex and striatum. Several nuclei, such as the caudate-putamen and the CA1 field of the hippocampus, exhibited input preferences to different cell types in the amygdala. Notably, we identified several novel input areas, including the substantia innominata and zona incerta. These findings provide anatomical evidence to help understand the precise connections and diverse functions of the amygdala.

Distinct subtypes of inhibitory interneurons differentially promote the propagation of rate and temporal codes in the feedforward neural network.

Sensory information is believed to be encoded in neuronal spikes using two different neural codes, the rate code (spike firing rate) and the temporal code (precisely-timed spikes). Since the sensory cortex has a highly hierarchical feedforward structure, sensory information-carrying neural codes should reliably propagate across the feedforward network (FFN) of the cortex. Experimental evidence suggests that inhibitory interneurons, such as the parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons, that have distinctively different electrophysiological and synaptic properties, modulate the neural codes during sensory information processing in the cortex. However, how PV and SST interneurons impact on the neural code propagation in the cortical FFN is unknown. We address this question by building a five-layer FFN model consisting of a physiologically realistic Hodgkin-Huxley-type models of excitatory neurons and PV/SST interneurons at different ratios. In response to different firing rate inputs (20-80 Hz), a higher ratio of PV over SST interneurons promoted a reliable propagation of all ranges of firing rate inputs. In contrast, in response to a range of precisely-timed spikes in the form of pulse-packets [with a different number of spikes (α, 40-400 spikes) and degree of dispersion (σ, 0-20 ms)], a higher ratio of SST over PV interneurons promoted a reliable propagation of pulse-packets. Our simulation results show that PV and SST interneurons differentially promote a reliable propagation of the rate and temporal codes, respectively, indicating that the dynamic recruitment of PV and SST interneurons may play critical roles in a reliable propagation of sensory information-carrying neural codes in the cortical FFN.

The lateralization of left hippocampal CA3 during the retrieval of spatial working memory.

The hippocampal CA3 contributes to spatial working memory (SWM), but which stage of SWM the CA3 neurons act on and whether the lateralization of CA3 function occurs in SWM is also unknown. Here, we reveal increased neural activity in both sample and choice phases of SWM. Left CA3 (LCA3) neurons show higher sensitivity in the choice phase during the correct versus error trials compared with right CA3 (RCA3) neurons. LCA3 initiates firing prior to RCA3 in the choice phase. Optogenetic suppression of pyramidal neurons in LCA3 disrupts SWM only in the choice phase. Furthermore, we discover that parvalbumin (PV) neurons, rather than cholinergic neurons in the medial septum (DB were cholinergic neurons), can project directly to unilateral CA3. Selective suppression of PV neurons in the MS projecting to LCA3 impairs SWM. The findings suggest that MSPV-LCA3 projection plays a crucial role in manipulating the lateralization of LCA3 in the retrieval of SWM.

Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior.

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior.

Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD).

Autism spectrum disorders (ASD) are persistent conditions resulting from disrupted/altered neurodevelopment. ASD multifactorial etiology-and its numerous comorbid conditions-heightens the difficulty in identifying its underlying causes, thus obstructing the development of effective therapies. Increasing evidence from both animal and human studies suggests an altered functioning of the parvalbumin (PV)-expressing inhibitory interneurons as a common and possibly unifying pathway for some forms of ASD. PV-expressing interneurons (short: PVALB neurons) are critically implicated in the regulation of cortical networks' activity. Their particular connectivity patterns, i.e., their preferential targeting of perisomatic regions and axon initial segments of pyramidal cells, as well as their reciprocal connections, enable PVALB neurons to exert a fine-tuned control of, e.g., spike timing, resulting in the generation and modulation of rhythms in the gamma range, which are important for sensory perception and attention.New methodologies such as induced pluripotent stem cells (iPSC) and genome-editing techniques (CRISPR/Cas9) have proven to be valuable tools to get mechanistic insight in neurodevelopmental and/or neurodegenerative and neuropsychiatric diseases. Such technological advances have enabled the generation of PVALB neurons from iPSC. Tagging of these neurons would allow following their fate during the development, from precursor cells to differentiated (and functional) PVALB neurons. Also, it would enable a better understanding of PVALB neuron function, using either iPSC from healthy donors or ASD patients with known mutations in ASD risk genes. In this concept paper, the strategies hopefully leading to a better understanding of PVALB neuron function(s) are briefly discussed. We envision that such an iPSC-based approach combined with emerging (genetic) technologies may offer the opportunity to investigate in detail the role of PVALB neurons and PV during "neurodevelopment ex vivo."

Accelerated Hyper-Maturation of Parvalbumin Circuits in the Absence of MeCP2.

Methyl-CpG-binding protein 2 (MeCP2) mutations are the primary cause of Rett syndrome, a severe neurodevelopmental disorder. Cortical parvalbumin GABAergic interneurons (PV) make exuberant somatic connections onto pyramidal cells in the visual cortex of Mecp2-deficient mice, which contributes to silencing neuronal cortical circuits. This phenotype can be rescued independently of Mecp2 by environmental, pharmacological, and genetic manipulation. It remains unknown how Mecp2 mutation can result in abnormal inhibitory circuit refinement. In the present manuscript, we examined the development of GABAergic circuits in the primary visual cortex of Mecp2-deficient mice. We identified that PV circuits were the only GABAergic interneurons to be upregulated, while other interneurons were downregulated. Acceleration of PV cell maturation was accompanied by increased PV cells engulfment by perineuronal nets (PNNs) and by an increase of PV cellular and PNN structural complexity. Interestingly, selective deletion of Mecp2 from PV cells was sufficient to drive increased structure complexity of PNN. Moreover, the accelerated PV and PNN maturation was recapitulated in organotypic cultures. Our results identify a specific timeline of disruption of GABAergic circuits in the absence of Mecp2, indicating a possible cell-autonomous role of MeCP2 in the formation of PV cellular arbors and PNN structures in the visual cortex.

Differential distributions of parvalbumin-positive interneurons in the sulci and gyri of the adult ferret cerebral cortex.

Although accumulating evidence suggests that there are significant anatomical and histological differences between the sulci and gyri of the cerebral cortex, whether there is a difference in the distribution of interneurons between the two cortical regions remains largely unknown. In this study, we systematically compared the distributions of parvalbumin-positive interneurons among three neighboring gyrus and sulcus pairs-coronal gyrus and cruciate sulcus, anterior ectosylvian gyrus and rostral suprasylvian sulcus, and posterior ectosylvian gyrus and pseudosylvian sulcus-in the adult ferret cerebral cortex. We proposed a method to partition sulci and gyri into several specific subregions through the deepest points of the sulci and the highest points of gyri in the inner and outer cortical contours of coronal sections. We found that the density of parvalbumin-positive interneurons in the gyri was significantly higher than that in the sulci. Further study revealed that the density of PV interneurons in superficial cortical layers (layers 2/3 and layer 4) was comparable among the three pairs of sulci and gyri. However, the density of parvalbumin-positive interneurons in cortical layers 5/6 was significantly higher in gyri than in sulci. These results indicate that parvalbumin-positive interneurons are differently distributed in infragranular layers of cortical sulci and gyri.

Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory.

The ability to identify strange conspecifics in societies is supported by social memory, which is vital for gregarious animals and humans. The function of hippocampal principal neurons in social memory has been extensively investigated; however, the nonprincipal neuronal mechanism underlying social memory remains unclear. Here, we first observed parallel changes in the ability for social recognition and the number of parvalbumin interneurons (PVIs) in the ventral CA1 (vCA1) after social isolation. Then, using tetanus toxin-mediated neuronal lesion and optogenetic stimulation approaches, we revealed that vCA1-PVIs specifically engaged in the retrieval stage of social memory. Finally, through the in vivo Ca2+ imaging technique, we demonstrated that vCA1-PVIs exhibited higher activities when subjected mice approached a novel mouse than to a familiar one. These results highlight the crucial role of vCA1-PVIs for distinguishing novel conspecifics from other individuals and contribute to our understanding of the neuropathology of mental diseases with social memory deficits.

Calcium Imaging of Parvalbumin Neurons in the Dorsal Root Ganglia.

We investigated the calcium dynamics of dorsal root ganglion (DRG) neurons using transgenic mice to target expression of the genetically encoded calcium indicator (GECI), GCaMP6s, to a subset of neurons containing parvalbumin (PV), a calcium-binding protein present in proprioceptors and low-threshold mechanoreceptors. This study provides the first analysis of GECI calcium transient parameters from large-diameter DRG neurons. Our approach generated calcium transients of consistent shape and time-course, with quantifiable characteristics. Four parameters of calcium transients were determined to vary independently from each other and thus are likely influenced by different calcium-regulating mechanisms: peak amplitude, rise time (RT), decay time, and recovery time. Pooled analysis of 188 neurons demonstrated unimodal distributions, providing evidence that PV+ DRG neurons regulate calcium similarly as a population despite their differences in size, electrical properties, and functional sensitivities. Calcium transients increased in size with elevated extracellular calcium, longer trains of action potentials, and higher stimulation frequencies. RT and decay time increased with the addition of the selective sarco/endoplasmic reticulum calcium ATPases (SERCA) blocker, thapsigargin (TG), while peak amplitude and recovery time remained the same. When elevating bath pH to 8.8 to block plasma-membrane calcium ATPases (PMCA), all measured parameters significantly increased. These results illustrate that GECI calcium transients provide sufficient resolution to detect changes in electrical activity and intracellular calcium concentration, as well as discern information about the activity of specific subclasses of calcium regulatory mechanisms.

Inducible and reversible silencing of the Pvalb gene in mice: An in vitro and in vivo study.

Inducible and reversible regulation of gene expression is a powerful approach for unraveling gene functions. Here, we describe the generation of a system to efficiently downregulate in a reversible and inducible manner the Pvalb gene coding for the calcium-binding protein parvalbumin (PV) in mice. We made use of an IPTG-inducible short hairpin RNA to activate Pvalb transcript knockdown and subsequently downregulate PV. The downregulation was rapidly reversed after withdrawal of IPTG. In vitro and in vivo experiments revealed a decrease in PV expression of ≥50% in the presence of IPTG and full reversibility after IPTG removal. We foresee that the tightly regulated and reversible PV downregulation in mice in vivo will provide a new tool for the control of Pvalb transcript expression in a temporal manner. Because PV protein and PVALB transcript levels were found to be lower in the brain of patients with autism spectrum disorder and schizophrenia, the novel transgenic mouse line might serve as a model to investigate the putative role of PV in these neurodevelopmental disorders.

Feedforward inhibition ahead of ictal wavefronts is provided by both parvalbumin- and somatostatin-expressing interneurons.

KEY POINTS: There is a rapid interneuronal response to focal activity in cortex, which restrains laterally propagating activity, including spreading epileptiform activity. The interneuronal response involves intense activation of both parvalbumin- and somatostatin-expressing interneurons. Interneuronal bursting is time-locked to glutamatergic barrages in the pre-ictal period. Ca2+ imaging using conditional expression of GCaMP6f provides an accurate readout of the evolving firing patterns in both types of interneuron. The activation profiles of the two interneuronal classes are temporally offset, with the parvalbumin population being activated first, and typically, at higher rates. ABSTRACT: Previous work has described powerful restraints on laterally spreading activity in cortical networks, arising from a rapid feedforward interneuronal response to focal activity. This response is particularly prominent ahead of an ictal wavefront. Parvalbumin-positive interneurons are considered to be critically involved in this feedforward inhibition, but it is not known what role, if any, is provided by somatostatin-expressing interneurons, which target the distal dendrites of pyramidal cells. We used a combination of electrophysiology and cell class-specific Ca2+ imaging in mouse brain slices bathed in 0 Mg2+ medium to characterize the activity profiles of pyramidal cells and parvalbumin- and somatostatin-expressing interneurons during epileptiform activation. The GCaMP6f signal strongly correlates with the level of activity for both interneuronal classes. Both interneuronal classes participate in the feedfoward inhibition. This contrasts starkly with the pattern of pyramidal recruitment, which is greatly delayed. During these barrages, both sets of interneurons show intense bursting, at rates up to 300Hz, which is time-locked to the glutamatergic barrages. The activity of parvalbumin-expressing interneurons appears to peak early in the pre-ictal period, and can display depolarizing block during the ictal event. In contrast, somatostatin-expressing interneuronal activity peaks significantly later, and firing persists throughout the ictal events. Interictal events appear to be very similar to the pre-ictal period, albeit with slightly lower firing rates. Thus, the inhibitory restraint arises from a coordinated pattern of activity in the two main classes of cortical interneurons.

Parvalbumin-Interneuron Output Synapses Show Spike-Timing-Dependent Plasticity that Contributes to Auditory Map Remodeling.

Parvalbumin (PV)-expressing interneurons mediate fast inhibition of principal neurons in many brain areas; however, long-term plasticity at PV-interneuron output synapses has been less well studied. In the auditory cortex, thalamic inputs drive reliably timed action potentials (APs) in principal neurons and PV-interneurons. Using paired recordings in the input layer of the mouse auditory cortex, we found a marked spike-timing-dependent plasticity (STDP) at PV-interneuron output synapses. Long-term potentiation of inhibition (iLTP) is observed upon postsynaptic (principal neuron) then presynaptic (PV-interneuron) AP firing. The opposite AP order causes GABAB-mediated long-term depression of inhibition (iLTD), which is developmentally converted to iLTP in an experience-dependent manner. Genetic deletion of GABAB receptors in principal neurons suppressed iLTD and produced deficits in auditory map remodeling. Output synapses of PV-interneurons thus show marked STDP, and one limb of this plasticity, GABAB-dependent iLTD, is a candidate mechanism for disinhibition during auditory critical period plasticity.

Electrophysiological properties and projections of lateral hypothalamic parvalbumin positive neurons.

Cracking the cytoarchitectural organization, activity patterns, and neurotransmitter nature of genetically-distinct cell types in the lateral hypothalamus (LH) is fundamental to develop a mechanistic understanding of how activity dynamics within this brain region are generated and operate together through synaptic connections to regulate circuit function. However, the precise mechanisms through which LH circuits orchestrate such dynamics have remained elusive due to the heterogeneity of the intermingled and functionally distinct cell types in this brain region. Here we reveal that a cell type in the mouse LH identified by the expression of the calcium-binding protein parvalbumin (PVALB; LHPV) is fast-spiking, releases the excitatory neurotransmitter glutamate, and sends long range projections throughout the brain. Thus, our findings challenge long-standing concepts that define neurons with a fast-spiking phenotype as exclusively GABAergic. Furthermore, we provide for the first time a detailed characterization of the electrophysiological properties of these neurons. Our work identifies LHPV neurons as a novel functional component within the LH glutamatergic circuitry.

Dichotomous parvalbumin interneuron populations in dorsolateral and dorsomedial striatum.

KEY POINTS: There are two electrophysiological dichotomous populations of parvalbumin (PV) interneurons located in the dorsal striatum. Striatal PV interneurons in medial and lateral regions differ significantly in their intrinsic excitability. Parvalbumin interneurons in the dorsomedial striatum, but not in the dorsolateral striatum, receive afferent glutamatergic input from cingulate cortex. ABSTRACT: Dorsomedial striatum circuitry is involved in goal-directed actions or movements that become habits upon repetition, as encoded by the dorsolateral striatum. An inability to shift from habits can compromise action-control and prevent behavioural adaptation. Although these regions appear to be clearly behaviourally distinct, little is known about their distinct physiology. Parvalbumin (PV) interneurons are a major source of striatal inhibition and are usually considered as a homogeneous population in the entire dorsal striatum. In the present study, we recorded PV interneurons in dorsal striatum slices from wild-type male mice and suggest the existence of two electrophysiological dichotomous populations. We found that PV interneurons located at the dorsomedial striatum region have increased intrinsic excitability compared to PV interneurons in dorsolateral region. We also found that PV interneurons in the dorsomedial region, but not in the dorsolateral striatum region, receive short-latency excitatory inputs from cingulate cortex. Therefore, the results of the present study demonstrate the importance of considering region specific parvalbumin interneuron populations when studying dorsal striatal function.