RESUMEN
Interneurons in the medial prefrontal cortex (PFC) regulate local neural activity to influence cognitive, motivated, and emotional behaviors. Parvalbumin-expressing (PV+) interneurons are the primary mediators of thalamus-evoked feed-forward inhibition across the mouse cortex, including the anterior cingulate cortex, where they are engaged by inputs from the mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic (PL) cortex, we find that PV+ interneurons are scarce in the principal thalamorecipient layer 3 (L3), suggesting distinct mechanisms of inhibition. To identify the interneurons that mediate MD-evoked inhibition in PL, we combine slice physiology, optogenetics, and intersectional genetic tools in mice of both sexes. We find interneurons expressing cholecystokinin (CCK+) are abundant in L3 of PL, with cells exhibiting fast-spiking (fs) or non-fast-spiking (nfs) properties. MD inputs make stronger connections onto fs-CCK+ interneurons, driving them to fire more readily than nearby L3 pyramidal cells and other interneurons. CCK+ interneurons in turn make inhibitory, perisomatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feed-forward inhibition, but not direct excitation, is also sensitive to CB1R modulation. Our findings indicate that CCK+ interneurons contribute to MD-evoked inhibition in PL, revealing a mechanism by which cannabinoids can modulate MD-PFC communication.
Asunto(s)
Colecistoquinina , Interneuronas , Inhibición Neural , Corteza Prefrontal , Animales , Interneuronas/fisiología , Colecistoquinina/metabolismo , Corteza Prefrontal/fisiología , Ratones , Masculino , Femenino , Inhibición Neural/fisiología , Tálamo/fisiología , Ratones Endogámicos C57BL , Parvalbúminas/metabolismo , Ratones Transgénicos , Vías Nerviosas/fisiología , OptogenéticaRESUMEN
The algorithms and neural circuits that process spatio-temporal changes in luminance to extract visual motion cues have been the focus of intense research. An influential model, the Hassenstein-Reichardt correlator, relies on differential temporal filtering of two spatially separated input channels, delaying one input signal with respect to the other. Motion in a particular direction causes these delayed and non-delayed luminance signals to arrive simultaneously at a subsequent processing step in the brain; these signals are then nonlinearly amplified to produce a direction-selective response. Recent work in Drosophila has identified two parallel pathways that selectively respond to either moving light or dark edges. Each of these pathways requires two critical processing steps to be applied to incoming signals: differential delay between the spatial input channels, and distinct processing of brightness increment and decrement signals. Here we demonstrate, using in vivo patch-clamp recordings, that four medulla neurons implement these two processing steps. The neurons Mi1 and Tm3 respond selectively to brightness increments, with the response of Mi1 delayed relative to Tm3. Conversely, Tm1 and Tm2 respond selectively to brightness decrements, with the response of Tm1 delayed compared with Tm2. Remarkably, constraining Hassenstein-Reichardt correlator models using these measurements produces outputs consistent with previously measured properties of motion detectors, including temporal frequency tuning and specificity for light versus dark edges. We propose that Mi1 and Tm3 perform critical processing of the delayed and non-delayed input channels of the correlator responsible for the detection of light edges, while Tm1 and Tm2 play analogous roles in the detection of moving dark edges. Our data show that specific medulla neurons possess response properties that allow them to implement the algorithmic steps that precede the correlative operation in the Hassenstein-Reichardt correlator, revealing elements of the long-sought neural substrates of motion detection in the fly.
Asunto(s)
Drosophila melanogaster/fisiología , Percepción de Movimiento/fisiología , Vías Visuales/fisiología , Algoritmos , Animales , Oscuridad , Drosophila melanogaster/citología , Iluminación , Modelos Neurológicos , Neuronas/citología , Neuronas/fisiología , Técnicas de Placa-Clamp , Estimulación Luminosa , Retina/citología , Retina/fisiología , Vías Visuales/citologíaRESUMEN
Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at subpopulations of projection neurons and interneurons remains unresolved. Here, we examine D1 receptor expression and modulation at specific cell types and layers in the mouse prelimbic PFC. We first show that D1 receptors are enriched in pyramidal cells in both layers 5 and 6, and that these cells project to intratelencephalic targets including contralateral cortex, striatum, and claustrum rather than to extratelencephalic structures. We then find that D1 receptors are also present in interneurons and enriched in superficial layer VIP-positive (VIP+) interneurons that coexpresses calretinin but absent from parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons. Finally, we determine that D1 receptors strongly and selectively enhance action potential firing in only a subset of these corticocortical neurons and VIP+ interneurons. Our findings define several novel subpopulations of D1+ neurons, highlighting how modulation via D1 receptors can influence both excitatory and disinhibitory microcircuits in the PFC.
Asunto(s)
Interneuronas/citología , Neuronas Eferentes/citología , Corteza Prefrontal/citología , Receptores de Dopamina D1/análisis , Animales , Femenino , Interneuronas/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neuronas Eferentes/metabolismo , Corteza Prefrontal/metabolismo , Receptores de Dopamina D1/metabolismoRESUMEN
Inputs from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) play a key role in working memory and emotional control. However, little is known about how excitatory inputs from the vHPC engage different populations of neurons in the PFC. Here we use optogenetics and whole-cell recordings to study the cell-type specificity of synaptic connections in acute slices from the mouse PFC. We first show that vHPC inputs target pyramidal neurons whose cell bodies are located in layer (L)2/3 and L5 of infralimbic (IL) PFC, but only in L5 of prelimbic (PL) PFC, and not L6 of either IL or PL. We then compare connections onto different classes of projection neurons located in these layers and subregions of PFC. We establish vHPC inputs similarly contact corticocortical (CC) and cortico-amygdala neurons in L2/3 of IL, but preferentially target CC neurons over cortico-pontine neurons in L5 of both IL and PL. Of all these neurons, we determine that vHPC inputs are most effective at driving action potential (AP) firing of CC neurons in L5 of IL. We also show this connection exhibits frequency-dependent facilitation, with repetitive activity enhancing AP firing of IL L5 CC neurons, even in the presence of feedforward inhibition. Our findings reveal how vHPC inputs engage defined populations of projection neurons in the PFC, allowing preferentially activation of the intratelencephalic network.SIGNIFICANCE STATEMENT We examined the impact of connections from the ventral hippocampus (vHPC) onto different projection neurons in the mouse prefrontal cortex (PFC). We found vHPC inputs were strongest at corticocortical neurons in layer 5 of infralimbic PFC, where they robustly evoked action potential firing, including during repetitive activity with intact feedforward inhibition.
Asunto(s)
Vías Aferentes/fisiología , Hipocampo/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Potenciales de Acción , Amígdala del Cerebelo/citología , Animales , Transporte Axonal , Channelrhodopsins/biosíntesis , Channelrhodopsins/genética , Channelrhodopsins/efectos de la radiación , Femenino , Genes Reporteros , Hipocampo/citología , Interneuronas/fisiología , Masculino , Ratones , Optogenética , Especificidad de Órganos , Técnicas de Placa-Clamp , Puente/citología , Corteza Prefrontal/citología , Células Piramidales/fisiología , Sinapsis/fisiología , Transmisión SinápticaRESUMEN
The nucleus accumbens (NAc) is critical for motivated behavior and is rewired following exposure to drugs of abuse. Medium spiny neurons (MSNs) in the NAc express either D1 or D2 receptors and project to distinct downstream targets. Differential activation of these MSNs depends on both excitation from long-range inputs and inhibition via the local circuit. Assessing how long-range excitatory inputs engage inhibitory circuitry is therefore important for understanding NAc function. Here, we use slice electrophysiology and optogenetics to study ventral hippocampal (vHPC)-evoked feedforward inhibition in the NAc of male and female mice. We find that vHPC-evoked excitation is stronger at D1+ than D1- MSNs, whereas inhibition is unbiased at the two cell types. vHPC inputs contact both parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons, but PV+ cells are preferentially activated. Moreover, suppressing PV+ interneurons indicates they are primarily responsible for vHPC-evoked inhibition. Finally, repeated cocaine exposure alters the excitation of D1+ and D1- MSNs, without concomitant changes to inhibition, shifting the excitation/inhibition balance. Together, our results highlight the contributions of multiple interneuron populations to feedforward inhibition in the NAc. Moreover, they demonstrate that inhibition provides a stable backdrop on which drug-evoked changes to excitation occur within this circuit.SIGNIFICANCE STATEMENT Given the importance of the nucleus accumbens (NAc) in reward learning and drug-seeking behaviors, it is critical to understand what controls the activity of cells in this region. While excitatory inputs to projection neurons in the NAc have been identified, it is unclear how the local inhibitory network becomes engaged. Here, we identify a sparse population of interneurons responsible for feedforward inhibition evoked by ventral hippocampal input and characterize their connections within the NAc. We also demonstrate that the balance of excitation and inhibition that projection neurons experience is altered by exposure to cocaine. Together, this work provides insight into the fundamental circuitry of this region as well as the effects of drugs of abuse.
Asunto(s)
Cocaína/administración & dosificación , Hipocampo/fisiología , Inhibición Neural , Plasticidad Neuronal , Neuronas/fisiología , Núcleo Accumbens/fisiología , Potenciales de Acción , Animales , Femenino , Hipocampo/efectos de los fármacos , Interneuronas/efectos de los fármacos , Interneuronas/fisiología , Locomoción/efectos de los fármacos , Masculino , Ratones Transgénicos , Inhibición Neural/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Optogenética , Parvalbúminas/metabolismo , Receptores de Dopamina D1/fisiología , Potenciales Sinápticos/efectos de los fármacosRESUMEN
Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.
Asunto(s)
Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Factor 4E Eucariótico de Iniciación/metabolismo , Biosíntesis de Proteínas , Sinapsis/metabolismo , Sinapsis/patología , Animales , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/patología , Conducta Animal/efectos de los fármacos , Dendritas/metabolismo , Dendritas/patología , Factor 4E Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Femenino , Hipocampo/metabolismo , Hidrazonas , Infusiones Intraventriculares , Masculino , Ratones , Ratones Transgénicos , Neostriado/metabolismo , Plasticidad Neuronal , Nitrocompuestos/administración & dosificación , Nitrocompuestos/farmacología , Nitrocompuestos/uso terapéutico , Corteza Prefrontal/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , Caperuzas de ARN/metabolismo , Tiazoles/administración & dosificación , Tiazoles/farmacología , Tiazoles/uso terapéuticoRESUMEN
UNLABELLED: Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. SIGNIFICANCE STATEMENT: The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections.
Asunto(s)
Complejo Nuclear Basolateral/fisiología , Inhibición Neural/fisiología , Neuronas/fisiología , Corteza Prefrontal/citología , Sinapsinas/fisiología , Potenciales Sinápticos/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Channelrhodopsins , Toxina del Cólera/metabolismo , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición Neural/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/clasificación , Parvalbúminas/genética , Parvalbúminas/metabolismo , Somatostatina/genética , Somatostatina/metabolismo , Sinapsinas/genética , Potenciales Sinápticos/efectos de los fármacos , Potenciales Sinápticos/genéticaRESUMEN
Cortical interneurons activate GABA-A receptors to rapidly control electrical and biochemical signaling at pyramidal neurons. Different populations of interneurons are known to uniquely target the soma and dendrites of pyramidal neurons. However, the ability of these interneurons to inhibit Ca(2+) signaling at spines and dendrites is largely unexplored. Here we use whole-cell recordings, two-photon microscopy, GABA uncaging and optogenetics to study dendritic inhibition at layer 5 (L5) pyramidal neurons in slices of mouse PFC. We first show that GABA-A receptors strongly inhibit action potential (AP)-evoked Ca(2+) signals at both spines and dendrites. We find robust inhibition over tens of milliseconds that spreads along the dendritic branch. However, we observe no difference in the amount of inhibition at neighboring spines and dendrites. We then examine the influence of interneurons expressing parvalbumin (PV), somatostatin (SOM), or 5HT3a receptors. We determine that these populations of interneurons make unique contacts onto the apical and basal dendrites of L5 pyramidal neurons. We also show that SOM and 5HT3a but not PV interneurons potently inhibit AP Ca(2+) signals via GABA-A receptors at both spines and dendrites. These findings reveal how multiple interneurons regulate local Ca(2+) signaling in pyramidal neurons, with implications for cortical function and disease.
Asunto(s)
Potenciales de Acción/fisiología , Señalización del Calcio/fisiología , Espinas Dendríticas/fisiología , Inhibición Neural/fisiología , Receptores de GABA-A/fisiología , Animales , Dendritas/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The medial prefrontal cortex (mPFC) plays a critical role in the control of cognition and emotion. Reciprocal circuits between the mPFC and basolateral amygdala (BLA) are particularly important for emotional control. However, the neurons and synapses that link these brain regions remain largely unknown. Here we examine long-range connections between the mouse mPFC and BLA, using whole-cell recordings, optogenetics, and two-photon microscopy. We first identify two non-overlapping populations of layer 2 pyramidal neurons that directly project to either the BLA or contralateral mPFC. We then show that pyramidal neurons projecting to the BLA receive much stronger excitatory inputs from this same brain region. We next assess the contributions of both presynaptic and postsynaptic mechanisms to this cell-type and input-specific connectivity. We use two-photon mapping to reveal differences in both the synaptic density and subcellular targeting of BLA inputs. Finally, we simulate and experimentally validate how the number, volume, and location of active spines all contribute to preferential synaptic drive. Together, our findings reveal a novel and strong reciprocal circuit that is likely to be important for how the mPFC controls cognition and emotion.
Asunto(s)
Amígdala del Cerebelo/fisiología , Corteza Prefrontal/fisiología , Sinapsis/fisiología , Amígdala del Cerebelo/citología , Animales , Espinas Dendríticas/fisiología , Potenciales Postsinápticos Excitadores , Ratones , Microscopía de Fluorescencia por Excitación Multifotónica , Optogenética , Corteza Prefrontal/citología , Células Piramidales/fisiologíaRESUMEN
Glutamatergic inputs onto cortical pyramidal neurons are received and initially processed at dendritic spines. AMPA and NMDA receptors generate both synaptic potentials and calcium (Ca) signals in the spine head. These responses can in turn activate a variety of Ca, sodium (Na), and potassium (K) channels at spines. In principle, the roles of these receptors and channels can be strongly regulated by the subthreshold membrane potential. However, the impact of different receptors and channels has usually been studied at the level of dendrites. Much less is known about their influence at spines, where synaptic transmission and plasticity primarily occur. Here we examine single-spine responses in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon microscopy and two-photon uncaging, we first show that synaptic potentials and Ca signals differ at resting and near-threshold potentials. We then determine how subthreshold depolarizations alter the contributions of AMPA and NMDA receptors to synaptic responses. We show that voltage-sensitive Ca channels enhance synaptic Ca signals but fail to engage small-conductance Ca-activated K (SK) channels, which require greater numbers of inputs. Finally, we establish how the subthreshold membrane potential controls the ability of voltage-sensitive Na channels and K channels to influence synaptic responses. Our findings reveal how subthreshold depolarizations promote electrical and biochemical signaling at dendritic spines by regulating the contributions of multiple glutamate receptors and ion channels.
Asunto(s)
Espinas Dendríticas/fisiología , Potenciales de la Membrana/fisiología , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Sinapsis/fisiología , Animales , Calcio/metabolismo , Dendritas/efectos de los fármacos , Dendritas/fisiología , Espinas Dendríticas/efectos de los fármacos , Femenino , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones , Imagen Óptica , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/metabolismo , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Receptores AMPA/metabolismo , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Sinapsis/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Canales de Sodio Activados por Voltaje/metabolismoRESUMEN
Dopamine modulation in the prefrontal cortex is important for cognitive processing and disrupted in diverse neuropsychiatric diseases. Activation of D1 receptors is thought to enable working memory by enhancing the firing properties of pyramidal neurons. However, these receptors are only sparsely expressed in the prefrontal cortex, and how they impact individual neurons remains unknown. Here we study D1 receptor modulation of layer 5 pyramidal neurons in acute slices of the mouse prefrontal cortex. Using whole-cell recordings and two-photon microscopy, we show that neurons expressing D1 receptors have unique morphological and physiological properties. We then demonstrate that activation of these receptors selectively enhances the firing of these neurons by signaling via the protein kinase A pathway. This finding of robust D1 receptor modulation in only a subpopulation of neurons has important implications for cognitive function and disease.
Asunto(s)
Potenciales de Acción/fisiología , Corteza Prefrontal/citología , Células Piramidales/fisiología , Receptores de Dopamina D1/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Animales Recién Nacidos , Biofisica , Antagonistas de Dopamina/farmacología , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Antagonistas del GABA/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Transgénicos , Microscopía Confocal , Técnicas de Placa-Clamp , Piperazinas/farmacología , Lectinas de Plantas/genética , Células Piramidales/efectos de los fármacos , Piridazinas/farmacología , Quinoxalinas/farmacología , Receptores de Dopamina D1/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Pyramidal neurons in the prefrontal cortex (PFC) are important for the control of cognitive and emotional behavior. The medial PFC (mPFC) receives diverse long-range excitatory inputs from the midline thalamus, contralateral mPFC, basolateral amygdala, and ventral hippocampus. While axons from these different regions have distinct distributions in the mPFC, their functional connections at the cellular and subcellular levels remain unknown. Here, we use optogenetics to show that layer 2 pyramidal neurons in acute slices of the mouse mPFC receive excitatory inputs from each of these regions. Using a combination of optogenetics and two-photon microscopy, we then determine the subcellular properties of these inputs. We find that different types of inputs make selective contacts at the levels of both dendrites and spines. Using two-photon uncaging, we show that this subcellular targeting strongly influences synaptic efficacy in these neurons. Together, our results show that functional connectivity is finely tuned, with important implications for signal processing in the mPFC.
Asunto(s)
Corteza Prefrontal/citología , Corteza Prefrontal/fisiología , Células Piramidales/citología , Células Piramidales/fisiología , Sinapsis/fisiología , Sinapsis/ultraestructura , Transmisión Sináptica/fisiología , Animales , Células Cultivadas , Femenino , Masculino , Ratones , Vías Nerviosas/citología , Vías Nerviosas/fisiologíaRESUMEN
Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviors (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissect the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. Here, we report that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum reveals differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings uncover a cell-type-specific impact of the loss of fragile X messenger ribonucleoprotein (FMRP) on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS.
Asunto(s)
Trastorno del Espectro Autista , Síndrome del Cromosoma X Frágil , Animales , Humanos , Ratones , Síndrome del Cromosoma X Frágil/metabolismo , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Neuronas/metabolismo , Sinapsis/metabolismo , Ratones Noqueados , Modelos Animales de EnfermedadRESUMEN
Although primarily studied at the cell body, GABA(B) receptors (GABA(B)Rs) are abundant at spines and dendrites of cortical pyramidal neurons, where they are positioned to influence both synaptic and dendritic function. Here, we examine how GABA(B)Rs modulate calcium (Ca) signals evoked by action potentials (APs) in spines and dendrites of layer 2/3 pyramidal neurons in mouse prefrontal cortex. We first use two-photon microscopy to show that GABA(B)Rs inhibit AP Ca signals throughout the entire dendritic arbor of these neurons. We then use local pharmacology and GABA uncaging to show that dendritic GABA(B)Rs also decrease the input resistance, shorten the AP afterdepolarization, and generate inhibitory postsynaptic potentials. However, we find that these electrophysiological effects recorded at the cell body do not correlate with the inhibition of AP Ca signals measured in spines and dendrites. Instead, we use voltage-clamp recordings to show that GABA(B)Rs directly inhibit several subtypes of voltage-sensitive calcium channels (VSCCs) in both spines and dendrites. Given the importance of VSCC-mediated Ca signals for neuronal function, our results have implications for the functional role of dendritic GABA(B)Rs in the prefrontal cortex and throughout the brain.
Asunto(s)
Canales de Calcio/metabolismo , Dendritas/metabolismo , Espinas Dendríticas/metabolismo , Células Piramidales/metabolismo , Receptores de GABA-B/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Baclofeno/farmacología , Dendritas/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Electrofisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Agonistas de Receptores GABA-B/farmacología , Masculino , Ratones , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Células Piramidales/efectos de los fármacos , Estadísticas no ParamétricasRESUMEN
NMDA spikes are prominent in the basal dendrites of cortical pyramidal neurons and greatly expand their ability to integrate synaptic inputs. Calcium (Ca) signals during these spikes are important for synaptic plasticity and fundamentally depend on activation of NMDA receptors. However, the factors that shape the activation of these receptors and the initiation of NMDA spikes remain unclear. Here we examine the properties of NMDA spikes in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon imaging, we demonstrate that NMDA spikes evoke large Ca signals in both postsynaptic spines and nearby dendrites. We find that the dendrite Ca signals depend on NMDA and AMPA receptors but not sodium (Na) or Ca channels. Using voltage-clamp recordings, we show that activation of dendrite NMDA receptors is enhanced by concerted synaptic activity. Blocking glutamate reuptake further increases activation of these receptors and promotes the initiation of NMDA spikes. We conclude that glutamate spillover and recruitment of extrasynaptic receptors contribute to the initiation of NMDA spikes. These results have important implications for how synaptic activity generates both electrical and biochemical signals in dendrites and spines.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , N-Metilaspartato/farmacología , Células Piramidales/efectos de los fármacos , Animales , Animales Recién Nacidos , Ácido Aspártico/farmacología , Biofisica , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio/efectos de los fármacos , Quelantes/farmacología , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Sinergismo Farmacológico , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Estimulación Eléctrica/métodos , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Técnicas In Vitro , Indoles/farmacología , Masculino , Ratones , Técnicas de Placa-Clamp , Corteza Prefrontal/citología , Células Piramidales/citología , Quinoxalinas/farmacología , Estadísticas no ParamétricasRESUMEN
Connections from the basolateral amygdala (BLA) to medial prefrontal cortex (PFC) regulate memory and emotion and become disrupted in neuropsychiatric disorders. The diverse roles attributed to interactions between the BLA and PFC may reflect multiple circuits nested within a wider network. To examine these circuits, we first used retrograde and anterograde anatomy to show that the rostral BLA (rBLA) and caudal BLA (cBLA) differentially project to prelimbic (PL) and infralimbic (IL) subregions of the mouse PFC. Using ex vivo whole-cell recordings and optogenetics, we then assessed which neuronal subtypes are targeted, showing that rBLA preferentially drives layer 2 (L2) cortico-amygdalar (CA) neurons in PL, whereas cBLA drives layer 5 (L5) pyramidal tract (PT) neurons in IL. We next combined in vivo silicon probe recordings and optogenetics to confirm that cBLA mainly influences IL L5, whereas rBLA primarily activates PL L2, but also evokes polysynaptic activity in PL L5. Lastly, we used soma-tagged optogenetics to explore the local circuits linking superficial and deep layers of PL, showing how rBLA can engage L2 CA neurons to impact L5 PT neuron activity. Together, our findings delineate how subregions of the BLA target distinct networks within the PFC and differentially influence output from PL and IL.
Asunto(s)
Complejo Nuclear Basolateral , Ratones , Animales , Complejo Nuclear Basolateral/fisiología , Corteza Prefrontal/fisiología , Amígdala del Cerebelo/fisiología , Neuronas/fisiología , Células Piramidales/fisiología , Vías Nerviosas/fisiologíaRESUMEN
Cholinergic interneurons (ChIs) in the nucleus accumbens (NAc) play a central role in motivated behaviors and associated disorders. However, while the activation of ChIs has been well studied in the dorsal striatum, little is known about how they are engaged in the NAc. Here, we find that the ventral hippocampus (vHPC) and the paraventricular nucleus of the thalamus (PVT) are the main excitatory inputs to ChIs in the NAc medial shell. While the PVT activates ChIs, the vHPC evokes a pronounced pause in firing through prominent feedforward inhibition. In contrast to the dorsal striatum, this inhibition reflects strong connections onto ChIs from local parvalbumin interneurons. Our results reveal the mechanisms by which different long-range inputs engage ChIs, highlighting fundamental differences in local connectivity across the striatum.
Asunto(s)
Interneuronas , Núcleo Accumbens , Colinérgicos , Hipocampo/fisiología , Interneuronas/fisiología , Núcleo Accumbens/fisiología , ParvalbúminasRESUMEN
The prefrontal cortex (PFC) orchestrates higher brain function and becomes disrupted in many mental health disorders. The rodent medial PFC (mPFC) possesses an enormous variety of projection neurons and interneurons. These cells are engaged by long-range inputs from other brain regions involved in cognition, motivation, and emotion. They also communicate in the local network via specific connections between excitatory and inhibitory cells. In this review, we describe the cellular diversity of the rodent mPFC, the impact of long-range afferents, and the specificity of local microcircuits. We highlight similarities with and differences between other cortical areas, illustrating how the circuit organization of the mPFC may give rise to its unique functional roles.
Asunto(s)
Corteza Prefrontal , Roedores , Animales , Humanos , InterneuronasRESUMEN
Interactions between the thalamus and prefrontal cortex (PFC) play a critical role in cognitive function and arousal. Here, we use anatomical tracing, electrophysiology, optogenetics, and 2-photon Ca2+ imaging to determine how ventromedial (VM) and mediodorsal (MD) thalamus target specific cell types and subcellular compartments in layer 1 (L1) of mouse PFC. We find thalamic inputs make distinct connections in L1, where VM engages neuron-derived neurotrophic factor (NDNF+) cells in L1a and MD drives vasoactive intestinal peptide (VIP+) cells in L1b. These separate populations of L1 interneurons participate in different inhibitory networks in superficial layers by targeting either parvalbumin (PV+) or somatostatin (SOM+) interneurons. NDNF+ cells also inhibit the apical dendrites of L5 pyramidal tract (PT) cells to suppress action potential (AP)-evoked Ca2+ signals. Lastly, NDNF+ cells mediate a unique form of thalamus-evoked inhibition at PT cells, selectively blocking VM-evoked dendritic Ca2+ spikes. Together, our findings reveal how two thalamic nuclei differentially communicate with the PFC through distinct L1 micro-circuits.
Asunto(s)
Núcleo Talámico Mediodorsal/fisiología , Red Nerviosa/fisiología , Corteza Prefrontal/fisiología , Animales , Femenino , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Núcleo Talámico Mediodorsal/química , Núcleo Talámico Mediodorsal/citología , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/química , Red Nerviosa/citología , Optogenética/métodos , Corteza Prefrontal/química , Corteza Prefrontal/citologíaRESUMEN
Connections from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) regulate cognition, emotion, and memory. These functions are also tightly controlled by inhibitory networks in the PFC, whose disruption is thought to contribute to mental health disorders. However, relatively little is known about how the vHPC engages different populations of interneurons in the PFC. Here we use slice physiology and optogenetics to study vHPC-evoked feed-forward inhibition in the mouse PFC. We first show that cholecystokinin (CCK+), parvalbumin (PV+), and somatostatin (SOM+) expressing interneurons are prominent in layer 5 (L5) of infralimbic PFC. We then show that vHPC inputs primarily activate CCK+ and PV+ interneurons, with weaker connections onto SOM+ interneurons. CCK+ interneurons make stronger synapses onto pyramidal tract (PT) cells over nearby intratelencephalic (IT) cells. However, CCK+ inputs undergo depolarization-induced suppression of inhibition (DSI) and CB1 receptor modulation only at IT cells. Moreover, vHPC-evoked feed-forward inhibition undergoes DSI only at IT cells, confirming a central role for CCK+ interneurons. Together, our findings show how vHPC directly engages multiple populations of inhibitory cells in deep layers of the infralimbic PFC, highlighting unexpected roles for both CCK+ interneurons and endocannabinoid modulation in hippocampal-prefrontal communication.