Sensory Cortical Activity Is Related to the Selection of a Rhythmic Motor Action Pattern.

UNLABELLED: Rats produce robust, highly distinctive orofacial rhythms in response to taste stimuli-responses that aid in the consumption of palatable tastes and the ejection of aversive tastes, and that are sourced in a multifunctional brainstem central pattern generator. Several pieces of indirect evidence suggest that primary gustatory cortex (GC) may be a part of a distributed forebrain circuit involved in the selection of particular consumption-related rhythms, although not in the production of individual mouth movements per se. Here, we performed a series of tests of this hypothesis. We first examined the temporal relationship between GC activity and orofacial behaviors by performing paired single-neuron and electromyographic recordings in awake rats. Using a trial-by-trial analysis, we found that a subset of GC neurons shows a burst of activity beginning before the transition between nondistinct and taste-specific (i.e., consumption-related) orofacial rhythms. We further showed that shifting the latency of consumption-related behavior by selective cueing has an analogous impact on the timing of GC activity. Finally, we showed the complementary result, demonstrating that optogenetic perturbation of GC activity has a modest but significant impact on the probability that a specific rhythm will be produced in response to a strongly aversive taste. GC appears to be a part of a distributed circuit that governs the selection of taste-induced orofacial rhythms. SIGNIFICANCE STATEMENT: In many well studied (typically invertebrate) sensorimotor systems, top-down modulation helps motor-control regions "select" movement patterns. Here, we provide evidence that gustatory cortex (GC) may be part of the forebrain circuit that performs this function in relation to oral behaviors ("gapes") whereby a substance in the mouth is rejected as unpalatable. We show that GC palatability coding is well timed to play this role, and that the latency of these codes changes as the latency of gaping shifts with learning. We go on to show that by silencing these neurons, we can change the likelihood of gaping. These data help to break down the sensory/motor divide by showing a role for sensory cortex in the selection of motor behavior.

The Behavioral Relevance of Cortical Neural Ensemble Responses Emerges Suddenly.

Whereas many laboratory-studied decisions involve a highly trained animal identifying an ambiguous stimulus, many naturalistic decisions do not. Consumption decisions, for instance, involve determining whether to eject or consume an already identified stimulus in the mouth and are decisions that can be made without training. By standard analyses, rodent cortical single-neuron taste responses come to predict such consumption decisions across the 500 ms preceding the consumption or rejection itself; decision-related firing emerges well after stimulus identification. Analyzing single-trial ensemble activity using hidden Markov models, we show these decision-related cortical responses to be part of a reliable sequence of states (each defined by the firing rates within the ensemble) separated by brief state-to-state transitions, the latencies of which vary widely between trials. When we aligned data to the onset of the (late-appearing) state that dominates during the time period in which single-neuron firing is correlated to taste palatability, the apparent ramp in stimulus-aligned choice-related firing was shown to be a much more precipitous coherent jump. This jump in choice-related firing resembled a step function more than it did the output of a standard (ramping) decision-making model, and provided a robust prediction of decision latency in single trials. Together, these results demonstrate that activity related to naturalistic consumption decisions emerges nearly instantaneously in cortical ensembles. Significance statement: This paper provides a description of how the brain makes evaluative decisions. The majority of work on the neurobiology of decision making deals with "what is it?" decisions; out of this work has emerged a model whereby neurons accumulate information about the stimulus in the form of slowly increasing firing rates and reach a decision when those firing rates reach a threshold. Here, we study a different kind of more naturalistic decision--a decision to evaluate "what shall I do with it?" after the identity of a taste in the mouth has been identified--and show that this decision is not made through the gradual increasing of stimulus-related firing, but rather that this decision appears to be made in a sudden moment of "insight."

A Multisensory Network for Olfactory Processing.

Primary gustatory cortex (GC) is connected (both mono- and polysynaptically) to primary olfactory (piriform) cortex (PC)-connections that might be hypothesized to underlie the construction of a "flavor" percept when both gustatory and olfactory stimuli are present. Here we use multisite electrophysiology and optical inhibition of GC neurons (GCx, produced via infection with ArchT) to demonstrate that, indeed, during gustatory stimulation, taste-selective information is transmitted from GC to PC. We go on to show that these connections impact olfactory processing even in the absence of gustatory stimulation: GCx alters PC responses to olfactory stimuli presented alone, enhancing some and eliminating others, despite leaving the path from nasal epithelium to PC intact. Finally, we show the functional importance of this latter phenomenon, demonstrating that GCx renders rats unable to properly recognize odor stimuli. This sequence of findings suggests that sensory processing may be more intrinsically integrative than previously thought.

Lateral hypothalamus contains two types of palatability-related taste responses with distinct dynamics.

The taste of foods, in particular the palatability of these tastes, exerts a powerful influence on our feeding choices. Although the lateral hypothalamus (LH) has long been known to regulate feeding behavior, taste processing in LH remains relatively understudied. Here, we examined single-unit LH responses in rats subjected to a battery of taste stimuli that differed in both chemical composition and palatability. Like neurons in cortex and amygdala, LH neurons produced a brief epoch of nonspecific responses followed by a protracted period of taste-specific firing. Unlike in cortex, however, where palatability-related information only appears 500 ms after the onset of taste-specific firing, taste specificity in LH was dominated by palatability-related firing, consistent with LH's role as a feeding center. Upon closer inspection, taste-specific LH neurons fell reliably into one of two subtypes: the first type showed a reliable affinity for palatable tastes, low spontaneous firing rates, phasic responses, and relatively narrow tuning; the second type showed strongest modulation to aversive tastes, high spontaneous firing rates, protracted responses, and broader tuning. Although neurons producing both types of responses were found within the same regions of LH, cross-correlation analyses suggest that they may participate in distinct functional networks. Our data shed light on the implementation of palatability processing both within LH and throughout the taste circuit, and may ultimately have implications for LH's role in the formation and maintenance of taste preferences and aversions.

Acquisition of neural learning in cerebellum and cerebral cortex for smooth pursuit eye movements.

We evaluated the emergence of neural learning in the frontal eye fields (FEF(SEM)) and the floccular complex of the cerebellum while monkeys learned a precisely timed change in the direction of pursuit eye movement. For each neuron, we measured the time course of changes in neural response across a learning session that comprised at least 100 repetitions of an instructive change in target direction. In both areas, the average population learning curves tracked the behavioral changes with high fidelity, consistent with possible roles in driving learning. However, the learning curves of individual neurons sometimes bore little relation to the smooth, monotonic progression of behavioral learning. In the FEF(SEM), neural learning was episodic. For individual neurons, learning appeared at different times during the learning session and sometimes disappeared by the end of the session. Different FEF(SEM) neurons expressed maximal learning at different times relative to the acquisition of behavioral learning. In the floccular complex, many Purkinje cells acquired learned simple-spike responses according to the same time course as behavioral learning and retained their learned responses throughout the learning session. A minority of Purkinje cells acquired learned responses late in the learning session, after behavioral learning had reached an asymptote. We conclude that learning in single neurons can follow a very different time course from behavioral learning. Both the FEF(SEM) and the floccular complex contain representations of multiple temporal components of learning, with different neurons contributing to learning at different times during the acquisition of a learned movement.

Learned timing of motor behavior in the smooth eye movement region of the frontal eye fields.

Proper timing is a critical aspect of motor learning. We report a relationship between a representation of time and an expression of learned timing in neurons in the smooth eye movement region of the frontal eye fields (FEF(SEM)). During prelearning pursuit of target motion at a constant velocity, each FEF(SEM) neuron is most active at a distinct time relative to the onset of pursuit tracking. In response to an instructive change in target direction, a neuron expresses the most learning when the instruction occurs near the time of its maximal participation in prelearning pursuit. Different neurons are most active, and undergo the most learning, at distinct times during pursuit. We suggest that the representation of time in the FEF(SEM) drives learning that is temporally linked to an instructive change in target motion, and that this may be a general function of motor areas of the cortex.

A common motif targets huntingtin and the androgen receptor to the proteasome.

Huntington disease derives from a critically expanded polyglutamine tract in the huntingtin (Htt) protein; a similar polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy. AR activity also plays an essential role in prostate cancer. Molecular mechanisms that regulate Htt and AR degradation are not well understood but could have important therapeutic implications. We find that a pentapeptide motif (FQKLL) within the Htt protein regulates its degradation and subcellular localization to cytoplasm puncta. Disruption of the motif by alanine substitution at the hydrophobic residues increases the steady state level of the protein. Pulsechase analyses indicate that the motif regulates degradation. A similar motif (FQNLF) has corresponding activities in the AR protein. Transfer of the Htt motif with five flanking amino acids on either side to YFP reduces the steady state YFP level by rendering it susceptible to proteasome degradation. This work defines a novel proteasome-targeting motif that is necessary and sufficient to regulate the degradation of two disease-associated proteins.