RESUMEN
Histone proteins affect gene expression through multiple mechanisms, including through exchange with histone variants. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. Most notably, widely expressed variants of H2B remain elusive. We applied recently developed antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters, and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Further, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a mechanism linking histone variants to chromatin accessibility, transcriptional regulation, neuronal function, and memory. This work further identifies a widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.
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Cromatina , Histonas , Memoria a Largo Plazo , Neuronas , Sinapsis , Histonas/metabolismo , Histonas/genética , Animales , Cromatina/metabolismo , Cromatina/genética , Memoria a Largo Plazo/fisiología , Neuronas/metabolismo , Ratones , Sinapsis/metabolismo , Sinapsis/genética , Regiones Promotoras Genéticas , Ratones Endogámicos C57BL , Regulación de la Expresión Génica , Transcripción Genética , Masculino , HumanosRESUMEN
In humans, neuroligin-3 mutations are associated with autism, whereas in mice, the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse and thereby provide a plausible circuit substrate for autism pathophysiology.
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Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Animales , Trastorno Autístico/metabolismo , Ganglios Basales/metabolismo , Ganglios Basales/fisiopatología , Moléculas de Adhesión Celular Neuronal/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Mutación , Proteínas del Tejido Nervioso/metabolismo , Núcleo Accumbens/metabolismo , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Copy number variations (CNVs) in the Neurexin 1 (NRXN1) gene, which encodes a presynaptic protein involved in neurotransmitter release, are some of the most frequently observed single-gene variants associated with autism spectrum disorder (ASD). To address the functional contribution of NRXN1 CNVs to behavioral phenotypes relevant to ASD, we carried out systematic behavioral phenotyping of an allelic series of Nrxn1 mouse models: one carrying promoter and exon 1 deletion abolishing Nrxn1α transcription, one carrying exon 9 deletion disrupting Nrxn1α protein translation, and one carrying an intronic deletion with no observable effect on Nrxn1α expression. We found that homozygous loss of Nrxn1α resulted in enhanced aggression in males, reduced affiliative social behaviors in females, and significantly altered circadian activities in both sexes. Heterozygous or homozygous loss of Nrxn1α affected the preference for social novelty in male mice, and notably, enhanced repetitive motor skills and motor coordination in both sexes. In contrast, mice bearing an intronic deletion of Nrxn1 did not display alterations in any of the behaviors assessed. These findings demonstrate the importance of Nrxn1α gene dosage in regulating social, circadian, and motor functions, and the variables of sex and genomic positioning of CNVs in the expression of autism-related phenotypes. Importantly, mice with heterozygous loss of Nrxn1, as found in numerous autistic individuals, show an elevated propensity to manifest autism-related phenotypes, supporting the use of models with this genomic architecture to study ASD etiology and assess additional genetic variants associated with autism.
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Trastorno del Espectro Autista , Proteínas de Unión al Calcio , Moléculas de Adhesión de Célula Nerviosa , Animales , Femenino , Masculino , Ratones , Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN/genética , Fenotipo , Conducta Social , Moléculas de Adhesión de Célula Nerviosa/genética , Proteínas de Unión al Calcio/genéticaRESUMEN
Sensory cortices process stimuli in manners essential for perception. Very little is known regarding interactions between olfactory cortices. The piriform "primary" olfactory cortex, especially its anterior division (aPCX), extends dense association fibers into the ventral striatum's olfactory tubercle (OT), yet whether this corticostriatal pathway is capable of shaping OT activity, including odor-evoked activity, is unknown. Further unresolved is the synaptic circuitry and the spatial localization of OT-innervating PCX neurons. Here we build upon standing literature to provide some answers to these questions through studies in mice of both sexes. First, we recorded the activity of OT neurons in awake mice while optically stimulating principal neurons in the aPCX and/or their association fibers in the OT while the mice were delivered odors. This uncovered evidence that PCX input indeed influences OT unit activity. We then used patch-clamp recordings and viral tracing to determine the connectivity of aPCX neurons upon OT neurons expressing dopamine receptor types D1 or D2, two prominent cell populations in the OT. These investigations uncovered that both populations of neurons receive monosynaptic inputs from aPCX glutamatergic neurons. Interestingly, this input originates largely from the ventrocaudal aPCX. These results shed light on some of the basic physiological properties of this pathway and the cell-types involved and provide a foundation for future studies to identify, among other things, whether this pathway has implications for perception.SIGNIFICANCE STATEMENT Sensory cortices interact to process stimuli in manners considered essential for perception. Very little is known regarding interactions between olfactory cortices. The present study sheds light on some of the basic physiological properties of a particular intercortical pathway in the olfactory system and provides a foundation for future studies to identify, among other things, whether this pathway has implications for perception.
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Ácido Glutámico/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Tubérculo Olfatorio/metabolismo , Corteza Piriforme/metabolismo , Receptores de Dopamina D1/biosíntesis , Receptores de Dopamina D2/biosíntesis , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Odorantes , Neuronas Receptoras Olfatorias/efectos de los fármacos , Tubérculo Olfatorio/efectos de los fármacos , Corteza Piriforme/efectos de los fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Olfato/fisiologíaRESUMEN
The dorsomedial striatum, a key site of reward-sensitive motor output, receives extensive afferent input from cortex, thalamus and midbrain. These projections are integrated by striatal microcircuits containing both spiny projection neurons and local circuit interneurons. To explore target cell specificity of these projections, we compared inputs onto D1-dopamine receptor-positive spiny neurons, parvalbumin-positive fast-spiking interneurons and somatostatin-positive low-threshold-spiking interneurons, using cell type-specific rabies virus tracing and optogenetic-mediated projection neuron recruitment in mice. While the relative proportion of retrogradely labelled projection neurons was similar between target cell types, the convergence of inputs was systematically higher for projections onto fast-spiking interneurons. Rabies virus is frequently used to assess cell-specific anatomical connectivity but it is unclear how this correlates to synaptic connectivity and efficacy. To test this, we compared tracing data with target cell-specific measures of synaptic efficacy for anterior cingulate cortex and parafascicular thalamic projections using novel quantitative optogenetic measures. We found that target-specific patterns of convergence were extensively modified according to region of projection neuron origin and postsynaptic cell type. Furthermore, we observed significant divergence between cell type-specific anatomical connectivity and measures of excitatory synaptic strength, particularly for low-threshold-spiking interneurons. Taken together, this suggests a basic uniform connectivity map for striatal afferent inputs upon which presynaptic-postsynaptic interactions impose substantial diversity of physiological connectivity.
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Giro del Cíngulo/fisiología , Interneuronas/fisiología , Neostriado/fisiología , Red Nerviosa/fisiología , Neuronas Aferentes/fisiología , Tálamo/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , OptogenéticaRESUMEN
The zinc-finger SWIM domain-containing protein 6 (ZSWIM6) is a protein of unknown function that has been associated with schizophrenia and limited educational attainment by three independent genome-wide association studies. Additionally, a putatively causal point mutation in ZSWIM6 has been identified in several cases of acromelic frontonasal dysostosis with severe intellectual disability. Despite the growing number of studies implicating ZSWIM6 as an important regulator of brain development, its role in this process has never been examined. Here, we report the generation of Zswim6 knockout mice and provide a detailed anatomical and behavioral characterization of the resulting phenotype. We show that Zswim6 is initially expressed widely during embryonic brain development but becomes restricted to the striatum postnatally. Loss of Zswim6 causes a reduction in striatal volume and changes in medium spiny neuron morphology. These changes are associated with alterations in motor control, including hyperactivity, impaired rotarod performance, repetitive movements, and behavioral hyperresponsiveness to amphetamine. Together, our results show that Zswim6 is indispensable to normal brain function and support the notion that Zswim6 might serve as an important contributor to the pathogenesis of schizophrenia and other neurodevelopmental disorders.
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Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Proteínas de Unión al ADN/deficiencia , Hipercinesia/metabolismo , Hipercinesia/patología , Animales , Cuerpo Estriado/crecimiento & desarrollo , Proteínas de Unión al ADN/genética , Hipercinesia/genética , Locomoción/fisiología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/patologíaRESUMEN
Synaptic cell adhesion molecules, including the neurexin ligands, neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs), are thought to organize synapse assembly and specify synapse function. To test the synaptic role of these molecules in vivo, we performed lentivirally mediated knockdown of NL3, LRRTM1, and LRRTM2 in CA1 pyramidal cells of WT and NL1 KO mice at postnatal day (P)0 (when synapses are forming) and P21 (when synapses are largely mature). P0 knockdown of NL3 in WT or NL1 KO neurons did not affect excitatory synaptic transmission, whereas P0 knockdown of LRRTM1 and LRRTM2 selectively reduced AMPA receptor-mediated synaptic currents. P0 triple knockdown of NL3 and both LRRTMs in NL1 KO mice yielded greater reductions in AMPA and NMDA receptor-mediated currents, suggesting functional redundancy between NLs and LRRTMs during early synapse development. In contrast, P21 knockdown of LRRTMs did not alter excitatory transmission, whereas NL manipulations supported a role for NL1 in maintaining NMDA receptor-mediated transmission. These results show that neurexin ligands in vivo form a dynamic synaptic cell adhesion network, with compensation between NLs and LRRTMs during early synapse development and functional divergence upon synapse maturation.
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Moléculas de Adhesión Celular Neuronal/metabolismo , Adhesión Celular/fisiología , Hipocampo/fisiología , Sinapsis/metabolismo , Transmisión Sináptica/fisiología , Animales , Adhesión Celular/genética , Moléculas de Adhesión Celular Neuronal/genética , Técnicas de Silenciamiento del Gen , Vectores Genéticos/genética , Hipocampo/citología , Lentivirus , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Moléculas de Adhesión de Célula Nerviosa/genética , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Técnicas de Placa-Clamp , Transmisión Sináptica/genéticaRESUMEN
Striatal dopamine governs a wide range of behavioral functions, yet local dopamine concentrations can be dissociated from somatic activity. Here, we discuss how dopamine's diverse roles in behavior may be driven by local circuit mechanisms shaping dopamine release. We first look at historical and recent work demonstrating that striatal circuits interact with dopaminergic terminals to either initiate the release of dopamine or modulate the release of dopamine initiated by spiking in midbrain dopamine neurons, with particular attention to GABAergic and cholinergic local circuit mechanisms. Then we discuss some of the first in vivo studies of acetylcholine-dopamine interactions in striatum and broadly discuss necessary future work in understanding the roles of midbrain versus striatal dopamine regulation.
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Cuerpo Estriado , Dopamina , Dopamina/fisiología , Cuerpo Estriado/fisiología , Acetilcolina , Neuronas Dopaminérgicas/fisiologíaRESUMEN
Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories.1,2 Consequently, disruption of REM sleep after a traumatic event may increase the risk for developing PTSD.3,4 However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory.5 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories.
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Extinción Psicológica , Miedo , Sueño REM , Animales , Miedo/fisiología , Sueño REM/fisiología , Ratones , Extinción Psicológica/fisiología , Masculino , Ratones Endogámicos C57BL , Memoria/fisiología , Consolidación de la Memoria/fisiología , Condicionamiento Clásico/fisiología , Células Piramidales/fisiologíaRESUMEN
ABSTRACT: The thalamus plays an important role in sensory and motor information processing by mediating communication between the periphery and the cerebral cortex. Alterations in thalamic development have profound consequences on sensory and motor function. In this study, we investigated a mouse model in which thalamic nuclei formation is disrupted because of the absence of Sonic hedgehog (Shh) expression from 2 key signaling centers that are required for embryonic forebrain development. The resulting defects observed in distinct thalamic sensory nuclei in Shh mutant embryos persisted into adulthood prompting us to examine their effect on behavioral responses to somatosensory stimulation. Our findings reveal a role for first-order posterior medial thalamic neurons and their projections to layer 4 of the secondary somatosensory cortex in the transmission of nociceptive information. Together, these results establish a connection between a neurodevelopmental lesion in the thalamus and a modality-specific disruption in pain perception.
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Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs). These disorders often demonstrate male-specific vulnerabilities; however, the identification of underlying mechanisms remains a significant challenge in the field. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and mice modeling 16p11.2 del/+ exhibit sex-specific striatum-related phenotypes relevant to NDDs. Striatal circuits, crucial for locomotor control, consist of two distinct pathways: the direct and indirect pathways originating from D1 dopamine receptor (D1R) and D2 dopamine receptor (D2R) expressing spiny projection neurons (SPNs), respectively. In this study, we define the impact of 16p11.2 del/+ on striatal circuits in male and female mice. Using snRNA-seq, we identify sex- and cell type-specific transcriptomic changes in the D1- and D2-SPNs of 16p11.2 del/+ mice, indicating distinct transcriptomic signatures in D1-SPNs and D2-SPNs in males and females, with a â¼5-fold greater impact in males. Further pathway analysis reveals differential gene expression changes in 16p11.2 del/+ male mice linked to synaptic plasticity in D1- and D2-SPNs and GABA signaling pathway changes in D1-SPNs. Consistent with our snRNA-seq study revealing changes in GABA signaling pathways, we observe distinct changes in miniature inhibitory postsynaptic currents (mIPSCs) in D1- and D2-SPNs from 16p11.2 del/+ male mice. Behaviorally, we utilize conditional genetic approaches to introduce the hemideletion selectively in either D1- or D2-SPNs and find that conditional hemideletion of genes in the 16p11.2 region in D2-SPNs causes hyperactivity in male mice, but hemideletion in D1-SPNs does not. Within the striatum, hemideletion of genes in D2-SPNs in the dorsal lateral striatum leads to hyperactivity in males, demonstrating the importance of this striatal region. Interestingly, conditional 16p11.2 del/+ within the cortex drives hyperactivity in both sexes. Our work reveals that a locus linked to NDDs acts in different striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner, providing new insight into male vulnerability for NDDs. Highlights: - 16p11.2 hemideletion (16p11.2 del/+) induces sex- and cell type-specific transcriptomic signatures in spiny projection neurons (SPNs). - Transcriptomic changes in GABA signaling in D1-SPNs align with changes in inhibitory synapse function. - 16p11.2 del/+ in D2-SPNs causes hyperactivity in males but not females. - 16p11.2 del/+ in D2-SPNs in the dorsal lateral striatum drives hyperactivity in males. - 16p11.2 del/+ in cortex drives hyperactivity in both sexes.
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Regulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE, and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation, neuronal function, and memory. This work further identifies the first widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.
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Glioblastoma (GBM), a universally fatal brain cancer, infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression 1-6 . Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic 7-9 . The extent of integration of GBM cells into brain-wide neuronal circuitry is not well understood. Here we applied a rabies virus-mediated retrograde monosynaptic tracing approach 10-12 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrated into brain-wide neuronal circuits and exhibited diverse local and long-range connectivity. Beyond glutamatergic inputs, we identified a variety of neuromodulatory inputs across the brain, including cholinergic inputs from the basal forebrain. Acute acetylcholine stimulation induced sustained calcium oscillations and long-lasting transcriptional reprogramming of GBM cells into a more invasive state via the metabotropic CHRM3 receptor. CHRM3 downregulation suppressed GBM cell invasion, proliferation, and survival in vitro and in vivo. Together, these results reveal the capacity of human GBM cells to rapidly and robustly integrate into anatomically and molecularly diverse neuronal circuitry in the adult brain and support a model wherein rapid synapse formation onto GBM cells and transient activation of upstream neurons may lead to a long-lasting increase in fitness to promote tumor infiltration and progression.
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Fronto-striatal circuits have been implicated in cognitive control of behavioral output for social and appetitive rewards. The functional diversity of prefrontal cortical populations is strongly dependent on their synaptic targets, with control of motor output mediated by connectivity to dorsal striatum. Despite evidence for functional diversity along the anterior-posterior striatal axis, it is unclear how distinct fronto-striatal sub-circuits support value-based choice. Here we found segregated prefrontal populations defined by anterior/posterior dorsomedial striatal target. During a feedback-based 2-alternative choice task, single-photon imaging revealed circuit-specific representations of task-relevant information with prelimbic neurons targeting anterior DMS (PL::A-DMS) robustly modulated during choices and negative outcomes, while prelimbic neurons targeting posterior DMS (PL::P-DMS) encoded internal representations of value and positive outcomes contingent on prior choice. Consistent with this distributed coding, optogenetic inhibition of PL::A-DMS circuits strongly impacted choice monitoring and responses to negative outcomes while inhibition of PL::P-DMS impaired task engagement and strategies following positive outcomes. Together our data uncover PL populations engaged in distributed processing for value-based choice.
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Cuerpo Estriado , Neostriado , Ratones , Masculino , Animales , Cuerpo Estriado/fisiología , Corteza Prefrontal/fisiología , Inhibición PsicológicaRESUMEN
The ventral striatum is a reward center implicated in the pathophysiology of depression. It contains islands of Calleja, clusters of dopamine D3 receptor-expressing granule cells, predominantly in the olfactory tubercle (OT). These OT D3 neurons regulate self-grooming, a repetitive behavior manifested in affective disorders. Here we show that chronic restraint stress (CRS) induces robust depression-like behaviors in mice and decreases excitability of OT D3 neurons. Ablation or inhibition of these neurons leads to depression-like behaviors, whereas their activation ameliorates CRS-induced depression-like behaviors. Moreover, activation of OT D3 neurons has a rewarding effect, which diminishes when grooming is blocked. Finally, we propose a model that explains how OT D3 neurons may influence dopamine release via synaptic connections with OT spiny projection neurons (SPNs) that project to midbrain dopamine neurons. Our study reveals a crucial role of OT D3 neurons in bidirectionally mediating depression-like behaviors, suggesting a potential therapeutic target.
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Islotes Olfatorios , Estriado Ventral , Ratones , Animales , Depresión , Tubérculo Olfatorio , Neuronas DopaminérgicasRESUMEN
In a recent study, Bolkan, Stone, and colleagues demonstrated that direct and indirect striatal pathways in mice exert opponent control over choice behavior in a task- and state-dependent manner. This work highlights the need for rigorously controlled behavioral experiments and novel behavioral modeling in investigations of the neural mechanisms of decision making.
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Cognición , Cuerpo Estriado , Animales , Conducta de Elección , Toma de Decisiones , Ratones , Vías NerviosasRESUMEN
The thalamus is the principal information hub of the vertebrate brain, with essential roles in sensory and motor information processing, attention, and memory. The complex array of thalamic nuclei develops from a restricted pool of neural progenitors. We apply longitudinal single-cell RNA sequencing and regional abrogation of Sonic hedgehog (Shh) to map the developmental trajectories of thalamic progenitors, intermediate progenitors, and post-mitotic neurons as they coalesce into distinct thalamic nuclei. These data reveal that the complex architecture of the thalamus is established early during embryonic brain development through the coordinated action of four cell differentiation lineages derived from Shh-dependent and -independent progenitors. We systematically characterize the gene expression programs that define these thalamic lineages across time and demonstrate how their disruption upon Shh depletion causes pronounced locomotor impairment resembling infantile Parkinson's disease. These results reveal key principles of thalamic development and provide mechanistic insights into neurodevelopmental disorders resulting from thalamic dysfunction.
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Tálamo , Tálamo/citologíaRESUMEN
Neurexins are central to trans-synaptic cell adhesion and signaling during synapse specification and maintenance. The past two decades of human genetics research have identified structural variations in the neurexin gene family, in particular NRXN1 copy number variants (CNVs), implicated in multiple neuropsychiatric and developmental disorders. The heterogeneity and reduced penetrance of NRXN1 deletions, in addition to the pleiotropic, circuit-specific functions of NRXN1, present substantial obstacles to understanding how compromised NRXN1 function predisposes individuals to neuropsychiatric disorders. Here, we provide an updated review of NRXN1 genetics in disease, followed by recently published work using both human induced pluripotent stem cell (iPSC) derived systems and animal models to understand the mechanisms of disease pathophysiology. Finally, we suggest our outlook on how the field should progress to improve our understanding of neurexin mediated disease pathogenesis. We believe that understanding how structural genetic variants in NRXN1 contribute to disease pathophysiology requires parallel approaches in iPSC and mouse model systems, each leveraging their unique strengths - analysis of genetic interactions and background effects in iPSCs and neural circuit and behavioral analysis in mice.
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Proteínas de Unión al Calcio/fisiología , Variaciones en el Número de Copia de ADN , Trastornos Mentales/genética , Modelos Biológicos , Moléculas de Adhesión de Célula Nerviosa/fisiología , Animales , Genotipo , Humanos , Ratones , Mutación , FenotipoRESUMEN
Mutations in genes essential for synaptic function, such as the presynaptic adhesion molecule Neurexin1α (Nrxn1α), are strongly implicated in neuropsychiatric pathophysiology. As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control, and its impairment may represent a recurrent pathway to disease. Here, we test the functional relevance of Nrxn1α in striatal circuits by employing optogenetic-mediated afferent recruitment of dorsal prefrontal cortical (dPFC) and parafascicular thalamic connections onto dorsomedial striatal (DMS) spiny projection neurons (SPNs). For dPFC-DMS circuits, we find decreased synaptic strength specifically onto indirect pathway SPNs in both Nrxn1α+/- and Nrxn1α-/- mice, driven by reductions in neurotransmitter release. In contrast, thalamic excitatory inputs to DMS exhibit relatively normal excitatory synaptic strength despite changes in synaptic N-methyl-D-aspartate receptor (NMDAR) content. These findings suggest that dysregulation of Nrxn1α modulates striatal function in an input- and target-specific manner.
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Vías Aferentes/metabolismo , Proteínas de Unión al Calcio/metabolismo , Cuerpo Estriado/metabolismo , Sinapsis Eléctricas/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Transmisión Sináptica , Vías Aferentes/citología , Animales , Proteínas de Unión al Calcio/genética , Cuerpo Estriado/citología , Sinapsis Eléctricas/genética , Potenciales Postsinápticos Excitadores , Ácido Glutámico/metabolismo , Heterocigoto , Homocigoto , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Moléculas de Adhesión de Célula Nerviosa/genética , Optogenética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The dorsomedial striatum (DMS) is a central hub supporting goal-directed learning and motor performance. Recent evidence has revealed unexpected roles for local inhibitory GABAergic networks in modulating striatal output and behavior.1 The sparse low-threshold spiking interneuron subtype (LTSI), which exhibits robust reward-circumscribed population activity, is a bidirectional regulator of initial goal-directed learning.2 Striatal dopamine signaling is a central reward-related neuromodulatory system mediating goal-directed action and performance, serving as a teaching signal,3 facilitating synaptic plasticity,4 and invigorating motor behaviors.5 Given the dynamic modulation of LTSIs during goal-directed behavior, we hypothesized that they could provide a novel GABAergic mechanism of local striatal dopaminergic regulation to shape early learning. We provide anatomical evidence for close proximation of LTSI terminals and dopaminergic processes in striatum, suggesting that LTSIs directly control dopaminergic axon activity. Using in vitro fast scan cyclic voltammetry, we demonstrate that LTSIs directly attenuate optogenetically evoked dopamine via GABAB receptor signaling. In vivo, GRABDA dopamine sensor imaging shows that LTSIs strongly modulate striatal dopamine dynamics during operant learning, while pharmacological stabilization of dopamine via intra-striatal aripiprazole microinjection suppresses the effects of LTSI inhibition on learning. Together, these results uncover an unexpected function for LTSIs in gating striatal dopamine to facilitate goal-directed learning.