Single neuron responses to perceptual difficulty in the mouse auditory cortex.

Perceptual learning leads to improvement in behavioral performance, yet how the brain supports challenging perceptual demands is unknown. We used two photon imaging in the mouse primary auditory cortex during behavior in a Go-NoGo task designed to test perceptual difficulty. Using general linear model analysis, we found a subset of neurons that increased their responses during high perceptual demands. Single neurons increased their responses to both Go and NoGo sounds when mice were engaged in the more difficult perceptual discrimination. This increased responsiveness contributes to enhanced cortical network discriminability for the learned sounds. Under passive listening conditions, the same neurons responded weaker to the more similar sound pairs of the difficult task, and the training protocol by itself induced specific suppression to the learned sounds. Our findings identify how neuronal activity in auditory cortex is modulated during high perceptual demands, which is a fundamental feature associated with perceptual improvement.

Inference-Based Decisions in a Hidden State Foraging Task: Differential Contributions of Prefrontal Cortical Areas.

Essential features of the world are often hidden and must be inferred by constructing internal models based on indirect evidence. Here, to study the mechanisms of inference, we establish a foraging task that is naturalistic and easily learned yet can distinguish inference from simpler strategies such as the direct integration of sensory data. We show that both mice and humans learn a strategy consistent with optimal inference of a hidden state. However, humans acquire this strategy more than an order of magnitude faster than mice. Using optogenetics in mice, we show that orbitofrontal and anterior cingulate cortex inactivation impacts task performance, but only orbitofrontal inactivation reverts mice from an inference-based to a stimulus-bound decision strategy. These results establish a cross-species paradigm for studying the problem of inference-based decision making and begins to dissect the network of brain regions crucial for its performance.

Activation of serotonin neurons promotes active persistence in a probabilistic foraging task.

The neuromodulator serotonin (5-HT) has been implicated in a variety of functions that involve patience or impulse control. Many of these effects are consistent with a long-standing theory that 5-HT promotes behavioral inhibition, a motivational bias favoring passive over active behaviors. To further test this idea, we studied the impact of 5-HT in a probabilistic foraging task, in which mice must learn the statistics of the environment and infer when to leave a depleted foraging site for the next. Critically, mice were required to actively nose-poke in order to exploit a given site. We show that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus increases the willingness of mice to actively attempt to exploit a reward site before giving up. These results indicate that behavioral inhibition is not an adequate description of 5-HT function and suggest that a unified account must be based on a higher-order function.

Activity patterns of serotonin neurons underlying cognitive flexibility.

Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine-serotonin opponency with potential clinical implications.

Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons.

Serotonin (5-HT) is associated with mood and motivation but the function of endogenous 5-HT remains controversial. Here, we studied the impact of phasic optogenetic activation of 5-HT neurons in mice over time scales from seconds to weeks. We found that activating dorsal raphe nucleus (DRN) 5-HT neurons induced a strong suppression of spontaneous locomotor behavior in the open field with rapid kinetics (onset ≤1 s). Inhibition of locomotion was independent of measures of anxiety or motor impairment and could be overcome by strong motivational drive. Repetitive place-contingent pairing of activation caused neither place preference nor aversion. However, repeated 15 min daily stimulation caused a persistent increase in spontaneous locomotion to emerge over three weeks. These results show that 5-HT transients have strong and opposing short and long-term effects on motor behavior that appear to arise from effects on the underlying factors that motivate actions.

Optogenetic Activation of Dorsal Raphe Serotonin Neurons Rapidly Inhibits Spontaneous But Not Odor-Evoked Activity in Olfactory Cortex.

Serotonin (5-hydroxytriptamine; 5-HT) is implicated in a variety of brain functions including not only the regulation of mood and control of behavior but also the modulation of perception. 5-HT neurons in the dorsal raphe nucleus (DRN) often fire locked to sensory stimuli, but little is known about how 5-HT affects sensory processing, especially on this timescale. Here, we used an optogenetic approach to study the effect of 5-HT on single-unit activity in the mouse primary olfactory (anterior piriform) cortex. We show that activation of DRN 5-HT neurons rapidly inhibits the spontaneous firing of olfactory cortical neurons, acting in a divisive manner, but entirely spares sensory-driven firing. These results identify a new role for serotonergic modulation in dynamically regulating the balance between different sources of neural activity in sensory systems, suggesting a possible role for 5-HT in perceptual inference. SIGNIFICANCE STATEMENT: Serotonin is implicated in a wide variety of (pato)physiological functions including perception, but its precise role has remained elusive. Here, using optogenetic tools in vivo, we show that serotonergic neuromodulation prominently inhibits the spontaneous electrical activity of neurons in the primary olfactory cortex on a rapid (<1 s) timescale but leaves sensory responses unaffected. These results identify a new role for serotonergic modulation in rapidly changing the balance between different sources of neural activity in sensory systems.

Parallel coding schemes of whisker velocity in the rat's somatosensory system.

The function of rodents' whisker somatosensory system is to transform tactile cues, in the form of vibrissa vibrations, into neuronal responses. It is well established that rodents can detect numerous tactile stimuli and tell them apart. However, the transformation of tactile stimuli obtained through whisker movements to neuronal responses is not well-understood. Here we examine the role of whisker velocity in tactile information transmission and its coding mechanisms. We show that in anaesthetized rats, whisker velocity is related to the radial distance of the object contacted and its own velocity. Whisker velocity is accurately and reliably coded in first-order neurons in parallel, by both the relative time interval between velocity-independent first spike latency of rapidly adapting neurons and velocity-dependent first spike latency of slowly adapting neurons. At the same time, whisker velocity is also coded, although less robustly, by the firing rates of slowly adapting neurons. Comparing first- and second-order neurons, we find similar decoding efficiencies for whisker velocity using either temporal or rate-based methods. Both coding schemes are sufficiently robust and hardly affected by neuronal noise. Our results suggest that whisker kinematic variables are coded by two parallel coding schemes and are disseminated in a similar way through various brain stem nuclei to multiple brain areas.

Optogenetic recruitment of dorsal raphe serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice.

The inhibition of sensory responsivity is considered a core serotonin function, yet this hypothesis lacks direct support due to methodological obstacles. We adapted an optogenetic approach to induce acute, robust and specific firing of dorsal raphe serotonergic neurons. In vitro, the responsiveness of individual dorsal raphe serotonergic neurons to trains of light pulses varied with frequency and intensity as well as between cells, and the photostimulation protocol was therefore adjusted to maximize their overall output rate. In vivo, the photoactivation of dorsal raphe serotonergic neurons gave rise to a prominent light-evoked field response that displayed some sensitivity to a 5-HT1A agonist, consistent with autoreceptor inhibition of raphe neurons. In behaving mice, the photostimulation of dorsal raphe serotonergic neurons produced a rapid and reversible decrease in the animals' responses to plantar stimulation, providing a new level of evidence that serotonin gates sensory-driven responses.

A unifying framework underlying mechanotransduction in the somatosensory system.

Rodents use their whiskers to sense their surroundings. As most of the information available to the somatosensory system originates in whiskers' primary afferents, it is essential to understand the transformation of whisker motion into neuronal activity. Here, we combined in vivo recordings in anesthetized rats with mathematical modeling to ascertain the mechanical and electrical characteristics of mechanotransduction. We found that only two synergistic processes, which reflect the dynamic interactions between (1) receptor and whisker and (2) receptor and surrounding tissue, are needed to describe mechanotransduction during passive whiskers deflection. Interactions between these processes may account for stimulus-dependent changes in the magnitude and temporal pattern of tactile responses on multiple scales. Thus, we are able to explain complex electromechanical processes underlying sensory transduction using a simple model, which captures the responses of a wide range of mechanoreceptor types to diverse sensory stimuli. This compact and precise model allows for a ubiquitous description of how mechanoreceptors encode tactile stimulus.

Mechanisms of tactile information transmission through whisker vibrations.

In their natural environment, rodents use their whiskers to locate and distinguish between objects of different textures and shapes. They do so by moving their whiskers actively as well as passively, through body and head movements. To determine the mechanisms by which surface coarseness is translated into neuronal discharges through passive whisker movements, we monitored head movements of awake behaving rats while approaching objects. We then replayed these movements in anesthetized rats, monitored the whiskers' movements across various surfaces, and concurrently recorded the activity of first-order sensory neurons. We found that whiskers, being the first stage of sensory information translation, shape transduction by amplifying small-amplitude high-frequency signals. Thus, surface coarseness is transmitted through high-velocity micromotions. Consistent with this, we find that during surface contact, discrete high-velocity movements, or stick-slip events, evoke first-order neuronal discharge. Transient ringing in whiskers, which primarily represents resonance vibrations, follows these events, but seldom causes neurons to discharge. These sensory transformations are influenced by the whiskers' biomechanical properties. To determine the resemblance of these tactile transformations during passive whisker movements and active whisking, we induced artificial whisking across various surface textures. We found that the processes by which tactile information becomes available to the animal are similar for these different modes of behavior. Together, these findings indicate that the temporal bandpass properties for spike generation in first-order neurons are matched by the biomechanical characteristics of whiskers, which translate surface coarseness into high-frequency whisker micromotions. These properties enable rodents to acquire tactile information through passive and active movements of their whiskers.

Dynamic translation of surface coarseness into whisker vibrations.

Rodents in their natural environment use their whiskers to distinguish between surfaces having subtly different textures and shapes. They do so by actively sweeping their whiskers across surfaces in a rhythmic motion. To determine how textures are transformed into vibration signals in whiskers and how these vibrations are expressed in neuronal discharges, we induced active whisking in anesthetized rats, monitored the movement of whiskers across surfaces, and concurrently recorded from trigeminal ganglion (TG) neurons. We show that tactile information is transmitted through high-frequency micromotions superimposed on whisking macro motions. Consistent with this, we find that in most TG neurons, spike activity, and high-frequency micromotions are closely correlated. To determine whether these vibration signals can support texture discrimination, we examined their dependence on surface roughness and found that both vibration signals carry information about surface coarseness. Despite a large variability in this translation process, different textures are translated into distinct vibrations profiles. These profiles depend on whiskers properties, on radial distance to the surface, and on whisking frequency. Using the characteristics of these signals, we employ linear discriminant analysis and found that all whiskers were able to discriminate between different textures. While deteriorating with radial distance, this classification did not depend on whisking frequency. Finally, increasing the number of whisks and integrating tactile information from multiple whiskers improved texture discrimination. These results indicate that surface roughness is translated into distinct whisker vibration signals that result in neuronal discharges. However, due to the dynamic nature of this translation process, we propose that texture discrimination may require the integration of signals from multiple spatial and temporal sensory channels to disambiguate surface roughness.