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Behavioral experience and flexibility are crucial for survival in a constantly changing environment. Despite evolutionary pressures to develop adaptive behavioral strategies in a dynamically changing sensory landscape, the underlying neural correlates have not been well explored. Here, we use genetically encoded voltage imaging to measure signals in primary somatosensory cortex (S1) during sensory learning and behavioral adaptation in the mouse. In response to changing stimulus statistics, mice adopt a strategy that modifies their detection behavior in a context dependent manner as to maintain reward expectation. Surprisingly, neuronal activity in S1 shifts from simply representing stimulus properties to transducing signals necessary for adaptive behavior in an experience dependent manner. Our results suggest that neuronal signals in S1 are part of an adaptive framework that facilitates flexible behavior as individuals gain experience, which could be part of a general scheme that dynamically distributes the neural correlates of behavior during learning.

Models of basal ganglia function predict that tonic inhibitory output to motor thalamus suppresses unwanted movements, and that a decrease in such activity leads to action selection. Further, for unilateral activity changes in the basal ganglia, a lateralized effect on contralateral movements can be expected due to ipsilateral thalamocortical connectivity. However, a direct test of these outcomes of thalamic inhibition has not been performed. To conduct such a direct test, we utilized rapid optogenetic activation and inactivation of the GABAergic output of the substantia nigra pars reticulata (SNr) to motor thalamus in male and female mice that were trained in a sensory cued left/right licking task. Directional licking tasks have previously been shown to depend on a thalamocortical feedback loop between ventromedial motor thalamus and antero-lateral premotor cortex. In confirmation of model predictions, we found that unilateral optogenetic inhibition of GABAergic output from the SNr, during ipsilaterally cued trials, biased decision making towards a contralateral lick without affecting motor performance. In contrast, optogenetic excitation of SNr terminals in motor thalamus resulted in an opposite bias towards the ipsilateral direction confirming a bidirectional effect of tonic nigral output on directional decision making. However, direct optogenetic excitation of neurons in the SNr resulted in bilateral movement suppression, which is in agreement with previous results that show such suppression for nigral terminals in the superior colliculus, which receives a bilateral projection from SNr.

Behavioral adaptation is a prerequisite for survival in a constantly changing sensory environment, but the underlying strategies and relevant variables driving adaptive behavior are not well understood. Many learning models and neural theories consider probabilistic computations as an efficient way to solve a variety of tasks, especially if uncertainty is involved. Although this suggests a possible role for probabilistic inference and expectation in adaptive behaviors, there is little if any evidence of this relationship experimentally. Here, we investigated adaptive behavior in the rat model by using a well controlled behavioral paradigm within a psychophysical framework to predict and quantify changes in performance of animals trained on a simple whisker-based detection task. The sensory environment of the task was changed by transforming the probabilistic distribution of whisker deflection amplitudes systematically while measuring the animal's detection performance and corresponding rate of accumulated reward. We show that the psychometric function deviates significantly and reversibly depending on the probabilistic distribution of stimuli. This change in performance relates to accumulating a constant reward count across trials, yet it is exempt from changes in reward volume. Our simple model of reward accumulation captures the observed change in psychometric sensitivity and predicts a strategy seeking to maintain reward expectation across trials in the face of the changing stimulus distribution. We conclude that rats are able maintain a constant payoff under changing sensory conditions by flexibly adjusting their behavioral strategy. Our findings suggest the existence of an internal probabilistic model that facilitates behavioral adaptation when sensory demands change.SIGNIFICANCE STATEMENTThe strategy animals use to deal with a complex and ever-changing world is a key to understanding natural behavior. This study provides evidence that rodent behavioral performance is highly flexible in the face of a changing stimulus distribution, consistent with a strategy to maintain a desired accumulation of reward.

Models of basal ganglia function predict that tonic inhibitory output to motor thalamus suppresses unwanted movements, and that a decrease in such activity leads to action selection. A direct test of these outcomes of thalamic inhibition has not been performed, however. To conduct such a direct test, we utilized rapid optogenetic activation and inactivation of the GABAergic output of the substantia nigra pars reticulata (SNr) to motor thalamus in mice that were trained in a sensory cued left/right licking task. Directional licking tasks have previously been shown to depend on a thalamocortical feedback loop between ventromedial motor thalamus and antero-lateral premotor cortex (Li et al., 2015; Guo et al., 2017). In confirmation of model predictions, we found that 1s of unilateral optogenetic inhibition of GABAergic output from the SNr biased decision making towards the contralateral lick spout with ipsilaterally cued trials while leaving motor performance intact. In contrast, 1s of optogenetic excitation of SNr terminals in motor thalamus resulted in an opposite bias towards the ipsilateral direction confirming a bidirectional effect of tonic nigral output on directional decision making. In a second variant of the task we disallowed anticipatory licking and found that successful suppression of anticipatory licking was also impacted by our optogenetic manipulations in agreement with the suppressive effect of tonic nigral output. Nevertheless, direct unilateral excitation of SNr cell bodies resulted in bilateral movement suppression, suggesting that descending motor pathways from the SNr to superior colliculus also play an important role in the control of licking behavior.Significance StatementThis study provides the first evidence that basal ganglia output to motor thalamus can control decision making in left/right licking choices and suppress anticipatory movement initiation. Unilateral optogenetic inhibition or excitation of basal ganglia output via the substantia nigra resulted in opposite changes of directional lick choices and could override the sensory information on lick direction provided by a whisker stimulus. These results suggest that basal ganglia output gates activity in a thalamo-cortical feedback loop previously shown to underlie the control of forced choice directional licking behavior. The results substantiate models stating that tonic inhibition of motor thalamus from the basal ganglia directs action selection and suppresses unwanted movements.

Little is known about whether information transfer at primary sensory thalamic nuclei is modified by behavioral context. Here we studied the influence of previous decisions/rewards on current choices and preceding spike responses of ventroposterior medial thalamus (VPm; the primary sensory thalamus in the rat whisker-related tactile system). We trained head-fixed rats to detect a ramp-like deflection of one whisker interspersed within ongoing white noise stimulation. Using generative modeling of behavior, we identify two task-related variables that are predictive of actual decisions. The first reflects task engagement on a local scale (“trial history”: defined as the decisions and outcomes of a small number of past trials), whereas the other captures behavioral dynamics on a global scale (“satiation”: slow dynamics of the response pattern along an entire session). Although satiation brought about a slow drift from Go to NoGo decisions during the session, trial history was related to local (trial-by-trial) patterning of Go and NoGo decisions. A second model that related the same predictors first to VPm spike responses, and from there to decisions, indicated that spiking, in contrast to behavior, is sensitive to trial history but relatively insensitive to satiation. Trial history influences VPm spike rates and regularity such that a history of Go decisions would predict fewer noise-driven spikes (but more regular ones), and more ramp-driven spikes. Neuronal activity in VPm, thus, is sensitive to local behavioral history, and may play an important role in higher-order cognitive signaling.SIGNIFICANCE STATEMENTIt is an important question for perceptual and brain functions to find out whether cognitive signals modulate the sensory signal stream and if so, where in the brain this happens. This study provides evidence that decision and reward history can already be reflected in the ascending sensory pathway, on the level of first-order sensory thalamus. Cognitive signals are relayed very selectively such that only local trial history (spanning a few trials) but not global history (spanning an entire session) are reflected.

Which physical parameter of vibrissa deflections is extracted by the rodent tactile system for discrimination? Particularly, it remains unclear whether perception has access to instantaneous kinematic parameters (i.e., the details of the trajectory) or relies on temporally integration of the movement trajectory such as frequency (e.g., spectral information) and intensity (e.g., mean speed). Here, we use a novel detection of change paradigm in head-fixed rats, which presents pulsatile vibrissa stimuli in seamless sequence for discrimination. This procedure ensures that processes of decision making can directly tap into sensory signals (no memory functions involved). We find that discrimination performance based on instantaneous kinematic cues far exceeds the ones provided by frequency and intensity. Neuronal modeling based on barrel cortex single units shows that small populations of sensitive neurons provide a transient signal that optimally fits the characteristic of the subject's perception. The present study is the first to show that perceptual read-out is superior in situations allowing the subject to base perception on detailed trajectory cues, that is, instantaneous kinematic variables. A possible impact of this finding on tactile systems of other species is suggested by evidence for instantaneous coding also in primates.

With the recent breakthrough in genetically expressed voltage indicators (GEVIs), there has been a tremendous demand to determine the capabilities of these sensors in vivo. Novel voltage sensitive fluorescent proteins allow for direct measurement of neuron membrane potential changes through changes in fluorescence. Here, we utilized ArcLight, a recently developed GEVI, and examined the functional characteristics in the widely used mouse somatosensory whisker pathway. We measured the resulting evoked fluorescence using a wide-field microscope and a CCD camera at 200 Hz, which enabled voltage recordings over the entire cortical region with high temporal resolution. We found that ArcLight produced a fluorescent response in the S1 barrel cortex during sensory stimulation at single whisker resolution. During wide-field cortical imaging, we encountered substantial hemodynamic noise that required additional post hoc processing through noise subtraction techniques. Over a period of 28 days, we found clear and consistent ArcLight fluorescence responses to a simple sensory input. Finally, we demonstrated the use of ArcLight to resolve cortical S1 sensory responses in the awake mouse. Taken together, our results demonstrate the feasibility of ArcLight as a measurement tool for mesoscopic, chronic imaging.

This paper describes experimental techniques with head-fixed, operantly conditioned rodents that allow the control of stimulus presentation and tracking of motor output at hitherto unprecedented levels of spatio-temporal precision. Experimental procedures for the surgery and behavioral training are presented. We place particular emphasis on potential pitfalls using these procedures in order to assist investigators who intend to engage in this type of experiment. We argue that head-fixed rodent models, by allowing the combination of methodologies from molecular manipulations, intracellular electrophysiology, and imaging to behavioral measurements, will be instrumental in combining insights into the functional neuronal organization at different levels of observation. Provided viable behavioral methods are implemented, model systems based on rodents will be complementary to current primate models--the latter providing highest comparability with the human brain, while the former offer hugely advanced methodologies on the lower levels of organization, for example, genetic alterations, intracellular electrophysiology, and imaging.

Rodents use active whisker movements to explore their environment. The “slip hypothesis” of whisker-related tactile perception entails that short-lived kinematic events (abrupt whisker movements, called “slips”, due to bioelastic whisker properties that occur during active touch of textures) carry the decisive texture information. Supporting this hypothesis, previous studies have shown that slip amplitude and frequency occur in a texture-dependent way. Further, experiments employing passive pulsatile whisker deflections revealed that perceptual performance based on pulse kinematics (i.e., signatures that resemble slips) is far superior to the one based on time-integrated variables like frequency and intensity. So far, pulsatile stimuli were employed in a noise free environment. However, the realistic scenario involves background noise (e.g., evoked by rubbing across the texture). Therefore, if slips are used for tactile perception, the tactile neuronal system would need to differentiate slip-evoked spikes from those evoked by noise. To test the animals under these more realistic conditions, we presented passive whisker-deflections to head-fixed trained rats, consisting of “slip-like” events (waveforms mimicking slips occurring with touch of real textures) embedded into background noise. Varying the (i) shapes (ramp or pulse); (ii) kinematics (amplitude, velocity, etc.); and (iii) the probabilities of occurrence of slip-like events, we observed that rats could readily detect slip-like events of different shapes against noisy background. Psychophysical curves revealed that the difference of slip event and noise amplitude determined perception, while increased probability of occurrence (frequency) had barely any effect. These results strongly support the notion that encoding of kinematics dominantly determines whisker-related tactile perception while the computation of frequency or intensity plays a minor role.

Background: Carotid artery stenting (CAS) is associated with the risk of intraprocedural stroke. A better understanding of specific risk factors could help to improve the procedure and to reduce the overall risk of CAS. We addressed the role of carotid plaque echolucency as potential risk factor for cerebral embolism during CAS. Methods: We prospectively evaluated carotid plaque echolucency by use of a computer-assisted measure of echogenicity, the gray scale median (GSM), in 31 consecutive patients with symptomatic high-grade carotid stenosis that were scheduled to undergo CAS. Dual-frequency transcranial Doppler ultrasound was used to detect solid cerebral microemboli during CAS. Results: 27 of the 31 patients met all inclusion/exclusion criteria.Solid cerebral microemboli were detected during 17 of 27 CAS procedures. The GSM of the target plaques was lower in subjects with intraprocedural embolism (37.9 ± 20.8) than in those without (58.2 ± 25.7) (p = 0.040). A receiver-operating characteristic analysis showed that the GSM that gave the greatest separation between plaques with a higher and a lower probability of intraprocedural embolism was 50: the proportion of subjects with intraprocedural embolism was 85% in CAS of echolucent plaques (GSM Conclusions: CAS of both echolucent and echogenic carotid plaques may be associated with cerebral embolism, particularly CAS of echolucent plaques. Plaque echolucency alone does not reliably identify patients at particularly high risk of intraprocedural embolism, but should be considered as one of a broad panel of risk factors of CAS.