Decorrelating action of inhibition in neocortical networks.

Inhibitory GABAergic interneurons have been extensively studied but their contribution to circuit dynamics remain poorly understood. Although it has been suggested that interneurons, especially those belonging to the same subclass, synchronize their activity and impart this synchrony onto their local network, recent theoretical and experimental work have challenged this view. To better understand the activity of interneurons during cortical activity, we combined molecular identification, two-photon imaging, and electrophysiological recordings in thalamocortical slices from mouse somatosensory cortex. Using calcium imaging to monitor cortical activity, we found low spiking correlations among parvalbumin or somatostatin interneurons during cortical UP states, indicating that interneurons do not synchronize their firing. Intracellular recordings confirmed that nearby interneurons do not display more synchronous spiking than excitatory cells. The lack of interneuron synchrony was also evident during slow oscillations, even among interneurons that were electrically coupled via gap junctions, suggesting that their coupling does not function to synchronize their activity. Using voltage-clamp recordings from nearby pyramidal cells, we found that inhibitory currents (IPSCs) are more correlated than excitatory ones, but that correlated IPSCs arise from the activation of common presynaptic inhibitory cells, rather than from synchronization of interneuron activity. Finally, we demonstrate that pharmacologically reducing inhibitory currents increases correlated excitatory activity. We conclude that inhibitory interneurons do not have synchronous activity during UP states, and that their function may be to decorrelate rather than to synchronize the firing of neurons within the local network.

Cell-type specific auditory responses in the striatum are shaped by feed forward inhibition.

The posterior "tail" region of the striatum receives dense innervation from sensory brain regions and has been demonstrated to play a role in behaviors that require sensorimotor integration including discrimination 1,2 , avoidance 3 and defense 4 responses. The output neurons of the striatum, the D1 and D2 striatal projection neurons (SPNs) that make up the direct and indirect pathways, respectively, are thought to play differential roles in these behavioral responses, although it remains unclear if or how these neurons display differential responsivity to sensory stimuli. Here, we used whole-cell recordings in vivo and ex vivo to examine the strength of excitatory and inhibitory synaptic inputs onto D1 and D2 SPNs following the stimulation of upstream auditory pathways. While D1 and D2 SPNs both displayed stimulus-evoked depolarizations, D1 SPN responses were stronger and faster for all stimuli tested in vivo as well as in brain slices. This difference did not arise from differences in the strength of excitatory inputs but from differences in the strength of feed forward inhibition. Indeed, fast spiking interneurons, which are readily engaged by auditory afferents exerted stronger inhibition onto D2 SPNs compared to D1 SPNs. Our results support a model in which differences in feed forward inhibition enable the preferential recruitment of the direct pathway in response to auditory stimuli, positioning this pathway to initiate sound-driven actions.

Unraveling the dynamics of dopamine release and its actions on target cells.

The neuromodulator dopamine (DA) is essential for regulating learning, motivation, and movement. Despite its importance, however, the mechanisms by which DA influences the activity of target cells to alter behavior remain poorly understood. In this review, we describe recent methodological advances that are helping to overcome challenges that have historically hindered the field. We discuss how the employment of these methods is shedding light on the complex dynamics of extracellular DA in the brain, as well as how DA signaling alters the electrical, biochemical, and population activity of target neurons in vivo. These developments are generating novel hypotheses about the mechanisms through which DA release modifies behavior.

Cell Type-Specific Membrane Potential Changes in Dorsolateral Striatum Accompanying Reward-Based Sensorimotor Learning.

The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: (i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; (ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and (iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.

Fast nonnegative deconvolution for spike train inference from population calcium imaging.

Fluorescent calcium indicators are becoming increasingly popular as a means for observing the spiking activity of large neuronal populations. Unfortunately, extracting the spike train of each neuron from a raw fluorescence movie is a nontrivial problem. This work presents a fast nonnegative deconvolution filter to infer the approximately most likely spike train of each neuron, given the fluorescence observations. This algorithm outperforms optimal linear deconvolution (Wiener filtering) on both simulated and biological data. The performance gains come from restricting the inferred spike trains to be positive (using an interior-point method), unlike the Wiener filter. The algorithm runs in linear time, and is fast enough that even when simultaneously imaging >100 neurons, inference can be performed on the set of all observed traces faster than real time. Performing optimal spatial filtering on the images further refines the inferred spike train estimates. Importantly, all the parameters required to perform the inference can be estimated using only the fluorescence data, obviating the need to perform joint electrophysiological and imaging calibration experiments.

Acute changes in short-term plasticity at synapses with elevated levels of neuronal calcium sensor-1.

Short-term synaptic plasticity is a defining feature of neuronal activity, but the underlying molecular mechanisms are poorly understood. Depression of synaptic activity might be due to limited vesicle availability, whereas facilitation is thought to result from elevated calcium levels. However, it is unclear whether the strength and direction (facilitation versus depression) of plasticity at a given synapse result from preexisting synaptic strength or whether they are regulated by separate mechanisms. Here we show, in rat hippocampal cell cultures, that increases in the calcium binding protein neuronal calcium sensor-1 (NCS-1) can switch paired-pulse depression to facilitation without altering basal synaptic transmission or initial neurotransmitter release probability. Facilitation persisted during high-frequency trains of stimulation, indicating that NCS-1 can recruit 'dormant' vesicles. Our results suggest that NCS-1 acts as a calcium sensor for short-term plasticity by facilitating neurotransmitter output independent of initial release. We conclude that separate mechanisms are responsible for determining basal synaptic strength and short-term plasticity.

Cell-Type-Specific Sensorimotor Processing in Striatal Projection Neurons during Goal-Directed Behavior.

Goal-directed sensorimotor transformation drives important aspects of mammalian behavior. The striatum is thought to play a key role in reward-based learning and action selection, receiving glutamatergic sensorimotor signals and dopaminergic reward signals. Here, we obtain whole-cell membrane potential recordings from the dorsolateral striatum of mice trained to lick a reward spout after a whisker deflection. Striatal projection neurons showed strong task-related modulation, with more depolarization and action potential firing on hit trials compared to misses. Direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, exhibited a prominent early sensory response. Optogenetic stimulation of direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, readily substituted for whisker stimulation evoking a licking response. Our data are consistent with direct pathway striatonigral neurons contributing a "go" signal for goal-directed sensorimotor transformation leading to action initiation. VIDEO ABSTRACT.

Quantitative classification of somatostatin-positive neocortical interneurons identifies three interneuron subtypes.

Deciphering the circuitry of the neocortex requires knowledge of its components, making a systematic classification of neocortical neurons necessary. GABAergic interneurons contribute most of the morphological, electrophysiological and molecular diversity of the cortex, yet interneuron subtypes are still not well defined. To quantitatively identify classes of interneurons, 59 GFP-positive interneurons from a somatostatin-positive mouse line were characterized by whole-cell recordings and anatomical reconstructions. For each neuron, we measured a series of physiological and morphological variables and analyzed these data using unsupervised classification methods. PCA and cluster analysis of morphological variables revealed three groups of cells: one comprised of Martinotti cells, and two other groups of interneurons with short asymmetric axons targeting layers 2/3 and bending medially. PCA and cluster analysis of electrophysiological variables also revealed the existence of these three groups of neurons, particularly with respect to action potential time course. These different morphological and electrophysiological characteristics could make each of these three interneuron subtypes particularly suited for a different function within the cortical circuit.