RESUMO
During the critical period, neuronal connections are shaped by sensory experience. While the basis for this temporarily heightened plasticity remains unclear, shared connections introducing activity correlations likely play a key role. Thus, we investigated the changing intracortical connectivity in primary auditory cortex (A1) over development. In adult, layer 2/3 (L2/3) neurons receive ascending inputs from layer 4 (L4) and also receive few inputs from subgranular layer 5/6 (L5/6). We measured the spatial pattern of intracortical excitatory and inhibitory connections to L2/3 neurons in slices of mouse A1 across development using laser-scanning photostimulation. Before P11, L2/3 cells receive most excitatory input from within L2/3. Excitatory inputs from L2/3 and L4 increase after P5 and peak during P9-16. L5/6 inputs increase after P5 and provide most input during P12-16, the peak of the critical period. Inhibitory inputs followed a similar pattern. Functional circuit diversity in L2/3 emerges after P16. In vivo two-photon imaging shows low pairwise signal correlations in neighboring neurons before P11, which peak at P15-16 and decline after. Our results suggest that the critical period is characterized by high pairwise activity correlations and that transient hyperconnectivity of specific circuits, in particular those originating in L5/6, might play a key role.
Assuntos
Córtex Auditivo/fisiologia , Interneurônios/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Animais , Mapeamento Encefálico/métodos , Período Crítico Psicológico , Camundongos , Técnicas de Patch-Clamp/métodosRESUMO
OBJECTIVE: Common biological measurements are in the form of noisy convolutions of signals of interest with possibly unknown and transient blurring kernels. Examples include EEG and calcium imaging data. Thus, signal deconvolution of these measurements is crucial in understanding the underlying biological processes. The objective of this paper is to develop fast and stable solutions for signal deconvolution from noisy, blurred, and undersampled data, where the signals are in the form of discrete events distributed in time and space. METHODS: We introduce compressible state-space models as a framework to model and estimate such discrete events. These state-space models admit abrupt changes in the states and have a convergent transition matrix, and are coupled with compressive linear measurements. We consider a dynamic compressive sensing optimization problem and develop a fast solution, using two nested expectation maximization algorithms, to jointly estimate the states as well as their transition matrices. Under suitable sparsity assumptions on the dynamics, we prove optimal stability guarantees for the recovery of the states and present a method for the identification of the underlying discrete events with precise confidence bounds. RESULTS: We present simulation studies as well as application to calcium deconvolution and sleep spindle detection, which verify our theoretical results and show significant improvement over existing techniques. CONCLUSION: Our results show that by explicitly modeling the dynamics of the underlying signals, it is possible to construct signal deconvolution solutions that are scalable, statistically robust, and achieve high temporal resolution. SIGNIFICANCE: Our proposed methodology provides a framework for modeling and deconvolution of noisy, blurred, and undersampled measurements in a fast and stable fashion, with potential application to a wide range of biological data.
Assuntos
Algoritmos , Processamento de Sinais Assistido por Computador , Encéfalo/fisiologia , Sinalização do Cálcio/fisiologia , Eletroencefalografia/métodos , Humanos , Sono/fisiologiaRESUMO
Sensory environments change over a wide dynamic range and sensory processing can change rapidly to facilitate stable perception. While rapid changes may occur throughout the sensory processing pathway, cortical changes are believed to profoundly influence perception. Prior stimulation studies showed that orbitofrontal cortex (OFC) can modify receptive fields and sensory coding in A1, but the engagement of OFC during listening and the pathways mediating OFC influences on A1 are unknown. We show in mice that OFC neurons respond to sounds consistent with a role of OFC in audition. We then show in vitro that OFC axons are present in A1 and excite pyramidal and GABAergic cells in all layers of A1 via glutamatergic synapses. Optogenetic stimulation of OFC terminals in A1 in vivo evokes short-latency neural activity in A1 and pairing activation of OFC projections in A1 with sounds alters sound-evoked A1 responses. Together, our results identify a direct connection from OFC to A1 that can excite A1 neurons at the earliest stage of cortical processing, and thereby sculpt A1 receptive fields. These results are consistent with a role for OFC in adjusting to changing behavioral relevance of sensory inputs and modulating A1 receptive fields to enhance sound processing.
Assuntos
Córtex Auditivo/citologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Som , Estimulação Acústica , Potenciais de Ação/fisiologia , Animais , Percepção Auditiva , Axônios/fisiologia , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Potenciais Evocados/fisiologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tempo de Reação/fisiologiaRESUMO
Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as "patches" of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD.
Assuntos
Córtex Auditivo/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Animais , Córtex Auditivo/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/fisiologia , Tálamo/metabolismo , Tálamo/fisiopatologia , Ácido Valproico/metabolismoRESUMO
Activation of muscarinic acetylcholine (ACh) receptors (mAChRs) powerfully affects many neuronal properties as well as numerous cognitive behaviors. Small neuronal circuits constitute an intermediate level of organization between neurons and behaviors, and mAChRs affect interactions among cells that compose these circuits. Circuit activity is often assessed by extracellular recordings of the local field potentials (LFPs), which are analogous to in vivo EEGs, generated by coordinated neuronal interactions. Coherent forms of physiologically relevant circuit activity manifest themselves as rhythmic oscillations in the LFPs. Frequencies of rhythmic oscillations that are most closely associated with animal behavior are in the range of 4-80 Hz, which is subdivided into theta (4-14 Hz), beta (15-29 Hz) and gamma (30-80 Hz) bands. Activation of mAChRs triggers rhythmic oscillations in these bands in the hippocampus and neocortex. Inhibitory responses mediated by GABAergic interneurons constitute a prominent feature of these oscillations, and indeed, appear to be their major underlying factor in many cases. An important issue is which interneurons are involved in rhythm generation. Besides affecting cellular and network properties directly, mAChRs can cause the mobilization of endogenous cannabinoids (endocannabinoids, eCBs) that, by acting on the principal cannabinoid receptor of the brain, CB1R, regulate the release of certain neurotransmitters, including GABA. CB1Rs are heavily expressed on only a subset of interneurons and, at lower density, on glutamatergic neurons. Exogenous cannabinoids typically disrupt oscillations in the theta (θ) and gamma (γ) ranges, which probably contributes to the behavioral effects of these drugs. It is important to understand how neuronal circuit activity is affected by mAChR-driven eCBs, as this information will provide deeper insight into the actions of ACh itself, as well as into the effects of eCBs and exogenous cannabinoids in animal behavior. After covering some basic aspects of the mAChR system, this review will focus on recent findings concerning the mechanisms and circuitry that generate θ and γ rhythms in hippocampus and neocortex. The ability of optogenetic methods to probe the many roles of ACh in rhythm generation is highlighted.
RESUMO
Neuronal electrical oscillations in the theta (4-14 Hz) and gamma (30-80 Hz) ranges are necessary for the performance of certain animal behaviours and cognitive processes. Perisomatic GABAergic inhibition is prominently involved in cortical oscillations driven by ACh release from septal cholinergic afferents. In neocortex and hippocampal CA3 regions, parvalbumin (PV)-expressing basket cells, activated by ACh and glutamatergic agonists, largely mediate oscillations. However, in CA1 hippocampus in vitro, cholinergic agonists or the optogenetic release of endogenous ACh from septal afferents induces rhythmic, theta-frequency inhibitory postsynaptic currents (IPSCs) in pyramidal cells, even with glutamatergic transmission blocked. The IPSCs are regulated by exogenous and endogenous cannabinoids, suggesting that they arise from type 1 cannabinoid receptor-expressing (CB1R+) interneurons - mainly cholecystokinin (CCK)-expressing cells. Nevertheless, an occult contribution of PV-expressing interneurons to these rhythms remained conceivable. Here, we directly test this hypothesis by selectively silencing CA1 PV-expressing cells optogenetically with halorhodopsin or archaerhodopsin. However, this had no effect on theta-frequency IPSC rhythms induced by carbachol (CCh). In contrast, the silencing of glutamic acid decarboxylase 2-positive interneurons, which include the CCK-expressing basket cells, strongly suppressed inhibitory oscillations; PV-expressing interneurons appear to play no role. The low-frequency IPSC oscillations induced by CCh or optogenetically stimulated ACh release were also inhibited by a µ-opioid receptor (MOR) agonist, which was unexpected because MORs in CA1 are not usually associated with CCK-expressing cells. Our results reveal novel properties of an inhibitory oscillator circuit within CA1 that is activated by muscarinic agonists. The oscillations could contribute to behaviourally relevant, atropine-sensitive, theta rhythms and link cannabinoid and opioid actions functionally.
Assuntos
Analgésicos Opioides/farmacologia , Região CA1 Hipocampal/citologia , Canabinoides/farmacologia , Neurônios Colinérgicos/fisiologia , Potenciais Pós-Sinápticos Inibidores , Optogenética , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Colecistocinina/genética , Colecistocinina/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Interneurônios/fisiologia , Camundongos , Opsinas/genética , Opsinas/metabolismo , Parvalbuminas/genética , Parvalbuminas/metabolismo , Ritmo TetaRESUMO
Acetylcholine (ACh) influences a vast array of phenomena in cortical systems. It alters many ionic conductances and neuronal firing behavior, often by regulating membrane potential oscillations in populations of cells. Synaptic inhibition has crucial roles in many forms of oscillation, and cholinergic mechanisms regulate both oscillations and synaptic inhibition. In vitro investigations using bath-application of cholinergic receptor agonists, or bulk tissue electrical stimulation to release endogenous ACh, have led to insights into cholinergic function, but questions remain because of the relative lack of selectivity of these forms of stimulation. To investigate the effects of selective release of ACh on interneurons and oscillations, we used an optogenetic approach in which the light-sensitive non-selective cation channel, Channelrhodopsin2 (ChR2), was virally delivered to cholinergic projection neurons in the medial septum/diagonal band of Broca (MS/DBB) of adult mice expressing Cre-recombinase under the control of the choline-acetyltransferase (ChAT) promoter. Acute hippocampal slices obtained from these animals weeks later revealed ChR2 expression in cholinergic axons. Brief trains of blue light pulses delivered to untreated slices initiated bursts of ACh-evoked, inhibitory post-synaptic currents (L-IPSCs) in CA1 pyramidal cells that lasted for 10's of seconds after the light stimulation ceased. L-IPSC occurred more reliably in slices treated with eserine and a very low concentration of 4-AP, which were therefore used in most experiments. The rhythmic, L-IPSCs were driven primarily by muscarinic ACh receptors (mAChRs), and could be suppressed by endocannabinoid release from pyramidal cells. Finally, low-frequency oscillations (LFOs) of local field potentials (LFPs) were significantly cross-correlated with the L-IPSCs, and reversal of the LFPs near s. pyramidale confirmed that the LFPs were driven by perisomatic inhibition. This optogenetic approach may be a useful complementary technique in future investigations of endogenous ACh effects.
Assuntos
Acetilcolina/metabolismo , Hipocampo/fisiologia , Potenciais Pós-Sinápticos Inibidores/genética , Potenciais Pós-Sinápticos Inibidores/efeitos da radiação , Luz , Periodicidade , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Região CA1 Hipocampal/efeitos da radiação , Fibras Colinérgicas/efeitos dos fármacos , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/efeitos da radiação , Antagonistas de Receptores de GABA-A/farmacologia , Vetores Genéticos/genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos da radiação , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Camundongos , Antagonistas Muscarínicos/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Células Piramidais/efeitos da radiação , Receptor CB1 de Canabinoide/metabolismo , Rodopsina/genéticaRESUMO
Release of conventional neurotransmitters is mainly controlled by calcium (Ca²âº) influx via high-voltage-activated (HVA), Ca(v)2, channels ("N-, P/Q-, or R-types") that are opened by action potentials. Regulation of transmission by subthreshold depolarizations does occur, but there is little evidence that low-voltage-activated, Ca(v)3 ("T-type"), channels take part. GABA release from cortical perisomatic-targeting interneurons affects numerous physiological processes, and yet its underlying control mechanisms are not fully understood. We investigated whether T-type Ca²âº channels are involved in regulating GABA transmission from these cells in rat hippocampal CA1 using a combination of whole-cell voltage-clamp, multiple-fluorescence confocal microscopy, dual-immunolabeling electron-microscopy, and optogenetic methods. We show that Ca(v)3.1, T-type Ca²âº channels can be activated by α3ß4 nicotinic acetylcholine receptors (nAChRs) that are located on the synaptic regions of the GABAergic perisomatic-targeting interneuronal axons, including the parvalbumin-expressing cells. Asynchronous, quantal GABA release can be triggered by Ca²âº influx through presynaptic T-type Ca²âº channels, augmented by Ca²âº from internal stores, following focal microiontophoretic activation of the α3ß4 nAChRs. The resulting GABA release can inhibit pyramidal cells. The T-type Ca²âº channel-dependent mechanism is not dependent on, or accompanied by, HVA channel Ca²âº influx, and is insensitive to agonists of cannabinoid, µ-opioid, or GABA(B) receptors. It may therefore operate in parallel with the normal HVA-dependent processes. The results reveal new aspects of the regulation of GABA transmission and contribute to a deeper understanding of ACh and nicotine actions in CNS.