Balázs Hangya

Cortical interneurons that specialize in disinhibitory control

In the mammalian cerebral cortex the diversity of interneuronal subtypes underlies a division of labour subserving distinct modes of inhibitory control. A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation. Although several interneuron populations are known to target other interneurons to varying degrees, little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single-cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively. During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.

Phase Entrainment of Human Delta Oscillations Can Mediate the Effects of Expectation on Reaction Speed

The more we anticipate a response to a predictable stimulus, the faster we react. This empirical observation has been confirmed and quantified by many investigators suggesting that the processing of behaviorally relevant stimuli is facilitated by probability-based confidence of anticipation. However, the exact neural mechanisms underlying this phenomenon are largely unknown. Here we show that performance changes related to different levels of expectancy originate in dynamic modulation of delta oscillation phase. Our results obtained in rhythmic auditory target detection tasks indicated significant entrainment of the EEG delta rhythm to the onset of the target tones with increasing phase synchronization at higher levels of predictability. Reaction times correlated with the phase of the delta band oscillation at target onset. The fastest reactions occurred during the delta phase that most commonly coincided with the target event in the high expectancy conditions. These results suggest that low-frequency oscillations play a functional role in human anticipatory mechanisms, presumably by modulating synchronized rhythmic fluctuations in the excitability of large neuronal populations and by facilitating efficient task-related neuronal communication among brain areas responsible for sensory processing and response execution.

Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.

Neurons in the prefrontal cortex exhibit diverse behavioural correlates, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex. Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons. These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity.

GABAergic Neurons of the Medial Septum Lead the Hippocampal Network during Theta Activity

Information processing in the hippocampus critically relies on its reciprocal interaction with the medial septum (MS). Synchronization of the septo-hippocampal system was demonstrated during both major hippocampal activity states, the regular theta rhythm and the large amplitude irregular activity. Previous experimental and modeling data suggest that the MS provides rhythmic drive to the hippocampus, and hippocampo-septal feedback synchronizes septal pacemaker units. However, this view has recently been questioned based on the possibility of intrahippocampal theta genesis. Previously, we identified putative pacemaker neurons expressing parvalbumin (PV) and/or the pacemaker hyperpolarization-activated and cyclic nucleotide-gated nonselective cation channel (HCN) in the MS. In this study, by analyzing the temporal relationship of activity between the PV/HCN-containing medial septal neurons and hippocampal local field potential, we aimed to uncover whether the sequence of events during theta formation supports the classic view of septal drive or the challenging theory of hippocampal pacing of theta. Importantly, by implementing a circular statistical method, a temporal lead of these septal neurons over the hippocampus was observed on the course of theta synchronization. Moreover, the activity of putative hippocampal interneurons also preceded hippocampal local field theta, but by a shorter time period compared with PV/HCN-containing septal neurons. Using the concept of mutual information, the action potential series of PV/HCN-containing neurons shared higher amount of information with hippocampal field oscillation than PV/HCN-immunonegative cells. Thus, a pacemaker neuron population of the MS leads hippocampal activity, presumably via the synchronization of hippocampal interneurons.

Fast Synaptic Subcortical Control of Hippocampal Circuits

Subcortical Network Regulation Subcortical neuromodulatory centers dominate the motivational and emotional state–dependent control of cortical functions. Control of cortical circuits has been thought to involve a slow, diffuse neuromodulation that affects the excitability of large numbers of neurons relatively indiscriminately. Varga et al. (p. 449) describe a form of subcortical control of cortical information processing whereby strong, spatiotemporally precise excitatory input from midbrain serotonergic neurons produces a robust activation of hippocampal interneurons. This effect is mediated by a synaptic release of both serotonin and glutamate and impacts network activity patterns. A form of subcortical control of cortical information processing is mediated by a synaptic release of serotonin and glutamate. Cortical information processing is under state-dependent control of subcortical neuromodulatory systems. Although this modulatory effect is thought to be mediated mainly by slow nonsynaptic metabotropic receptors, other mechanisms, such as direct synaptic transmission, are possible. Yet, it is currently unknown if any such form of subcortical control exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory input from an ascending neuromodulatory center. Selective stimulation of serotonergic median raphe neurons produced a rapid activation of hippocampal interneurons. At the network level, this subcortical drive was manifested as a pattern of effective disynaptic GABAergic inhibition that spread throughout the circuit. This form of subcortical network regulation should be incorporated into current concepts of normal and pathological cortical function.

The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum.

The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm‐generating network. In recent studies the hyperpolarization‐activated, cyclic nucleotide‐gated non‐selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN‐expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)‐containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN‐expressing neurons. In contrast, only a minority of HCN‐negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV‐expressing HCN neurons had a marked bimodal phase distribution, whereas PV‐immunonegative HCN neurons did not show group‐level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN‐expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.

Convergence of Cortical and Sensory Driver Inputs on Single Thalamocortical Cells

Ascending and descending information is relayed through the thalamus via strong, “driver” pathways. According to our current knowledge, different driver pathways are organized in parallel streams and do not interact at the thalamic level. Using an electron microscopic approach combined with optogenetics and in vivo physiology, we examined whether driver inputs arising from different sources can interact at single thalamocortical cells in the rodent somatosensory thalamus (nucleus posterior, POm). Both the anatomical and the physiological data demonstrated that ascending driver inputs from the brainstem and descending driver inputs from cortical layer 5 pyramidal neurons converge and interact on single thalamocortical neurons in POm. Both individual pathways displayed driver properties, but they interacted synergistically in a time-dependent manner and when co-activated, supralinearly increased the output of thalamus. As a consequence, thalamocortical neurons reported the relative timing between sensory events and ongoing cortical activity. We conclude that thalamocortical neurons can receive 2 powerful inputs of different origin, rather than only a single one as previously suggested. This allows thalamocortical neurons to integrate raw sensory information with powerful cortical signals and transfer the integrated activity back to cortical networks.

From circuit motifs to computations: mapping the behavioral repertoire of cortical interneurons

The exquisite architecture of cortex incorporates a myriad of inhibitory interneuron types. Until recently, the dearth of techniques for cell type identification in awake animals has made it difficult to link interneuron activity with circuit function, computation and behavior. This situation has changed dramatically in recent years with the advent of novel tools for targeting genetically distinct interneuron types so their activity can be observed and manipulated. The association of different interneuron subtypes with specific circuit functions, such as gain modulation or disinhibition, is starting to reveal canonical circuit motifs conserved across neocortical regions. Moreover, it appears that some interneuron types are recruited at specific behavioral events and likely control the flow of information among and within brain areas at behavioral time scales. Based on these results we propose that interneuron function goes beyond network coordination and interneurons should be viewed as integral elements of cortical computations serving behavior.

Phase Advancement and Nucleus-Specific Timing of Thalamocortical Activity during Slow Cortical Oscillation

The exact timing of cortical afferent activity is instrumental for the correct coding and retrieval of internal and external stimuli. Thalamocortical inputs represent the most significant subcortical pathway to the cortex, but the precise timing and temporal variability of thalamocortical activity is not known. To examine this question, we studied the phase of thalamic action potentials relative to cortical oscillations and established correlations among phase, the nuclear location of the thalamocortical neurons, and the frequency of cortical activity. The phase of thalamic action potentials depended on the exact frequency of the slow cortical oscillation both on long (minutes) and short (single wave) time scales. Faster waves were accompanied by phase advancement in both cases. Thalamocortical neurons located in different nuclei fired at significantly different phases of the slow waves but were active at a similar phase of spindle oscillations. Different thalamic nuclei displayed distinct burst patterns. Bursts with a higher number of action potentials displayed progressive phase advancement in a nucleus-specific manner. Thalamic neurons located along nuclear borders were characterized by mixed burst and phase properties. Our data demonstrate that the temporal relationship between cortical and thalamic activity is not fixed but displays dynamic changes during oscillatory activity. The timing depends on the precise location and exact activity of thalamocortical cells and the ongoing cortical network pattern. This variability of thalamic output and its coupling to cortical activity can enable thalamocortical neurons to actively participate in the coding and retrieval of cortical signals.

Multiple Modes of Phase Locking between Sniffing and Whisking during Active Exploration

Sense organs are often actively controlled by motor processes and such active sensing profoundly shapes the timing of sensory information flow. The temporal coordination between different active sensing processes is less well understood but is essential for multisensory integration, coordination between brain regions, and energetically optimal sampling strategies. Here we studied the coordination between sniffing and whisking, the motor processes in rodents that control the acquisition of smell and touch information, respectively. Sniffing, high-frequency respiratory bouts, and whisking, rapid back and forth movements of mystacial whiskers, occur in the same theta frequency range (4–12 Hz) leading to a hypothesis that these sensorimotor rhythms are phase locked. To test this, we monitored sniffing using a thermocouple in the nasal cavity and whisking with an electromyogram of the mystacial pad in rats engaged in an open field reward foraging behavior. During bouts of exploration, sniffing and whisking showed strong one-to-one phase locking within the theta frequency range (4–12 Hz). Interestingly, we also observed multimode phase locking with multiple whisks within a sniff cycle or multiple sniffs within a whisk cycle—always at the same preferred phase. This specific phase relationship coupled the acquisition phases of the two sensorimotor rhythms, inhalation and whisker protraction. Our results suggest that sniffing and whisking may be under the control of interdependent rhythm generators that dynamically coordinate active acquisition of olfactory and somatosensory information.