In the first half of my talk, I will discuss our recent work on the midbrain dopamine system. The hypothesis that midbrain dopamine neurons broadcast an error signal for the prediction of reward is among the great successes of computational neuroscience. However, our recent results contradict a core aspect of this theory: that the neurons uniformly convey a scalar, global signal. I will review this work, as well as our new efforts to update models of the neural basis of reinforcement learning with our data. In the second half of my talk, I will discuss our recent findings of state-dependent decision-making mechanisms in the striatum.

The visual system of the brain is highly parallel in its architecture. This is clearly evident in the outputs of the retina, which arise from neurons called ganglion cells. Work in our lab has shown that mammalian retinas contain more than a dozen distinct types of ganglion cells. Each type appears to filter the retinal image in a unique way and to relay this processed signal to a specific set of targets in the brain. My students and I are working to understand the meaning of this parallel organization through electrophysiological and anatomical studies. We record from light-responsive ganglion cells in vitro using the whole-cell patch method. This allows us to correlate directly the visual response properties, intrinsic electrical behavior, synaptic pharmacology, dendritic morphology and axonal projections of single neurons. Other methods used in the lab include neuroanatomical tracing techniques, single-unit recording and immunohistochemistry. We seek to specify the total number of ganglion cell types, the distinguishing characteristics of each type, and the intraretinal mechanisms (structural, electrical, and synaptic) that shape their stimulus selectivities. Recent work in the lab has identified a bizarre new ganglion cell type that is also a photoreceptor, capable of responding to light even when it is synaptically uncoupled from conventional (rod and cone) photoreceptors. These ganglion cells appear to play a key role in resetting the biological clock. It is just this sort of link, between a specific cell type and a well-defined behavioral or perceptual function, that we seek to establish for the full range of ganglion cell types. My research concerns the structural and functional organization of retinal ganglion cells, the output cells of the retina whose axons make up the optic nerve. Ganglion cells exhibit great diversity both in their morphology and in their responses to light stimuli. On this basis, they are divisible into a large number of types (>15). Each ganglion-cell type appears to send its outputs to a specific set of central visual nuclei. This suggests that ganglion cell heterogeneity has evolved to provide each visual center in the brain with pre-processed representations of the visual scene tailored to its specific functional requirements. Though the outline of this story has been appreciated for some time, it has received little systematic exploration. My laboratory is addressing in parallel three sets of related questions: 1) How many types of ganglion cells are there in a typical mammalian retina and what are their structural and functional characteristics? 2) What combination of synaptic networks and intrinsic membrane properties are responsible for the characteristic light responses of individual types? 3) What do the functional specializations of individual classes contribute to perceptual function or to visually mediated behavior? To pursue these questions, we label retinal ganglion cells by retrograde transport from the brain; analyze in vitro their light responses, intrinsic membrane properties and synaptic pharmacology using the whole-cell patch clamp method; and reveal their morphology with intracellular dyes. Recently, we have discovered a novel ganglion cell in rat retina that is intrinsically photosensitive. These ganglion cells exhibit robust light responses even when all influences from classical photoreceptors (rods and cones) are blocked, either by applying pharmacological agents or by dissociating the ganglion cell from the retina. These photosensitive ganglion cells seem likely to serve as photoreceptors for the photic synchronization of circadian rhythms, the mechanism that allows us to overcome jet lag. They project to the circadian pacemaker of the brain, the suprachiasmatic nucleus of the hypothalamus. Their temporal kinetics, threshold, dynamic range, and spectral tuning all match known properties of the synchronization or "entrainment" mechanism. These photosensitive ganglion cells innervate various other brain targets, such as the midbrain pupillary control center, and apparently contribute to a host of behavioral responses to ambient lighting conditions. These findings help to explain why circadian and pupillary light responses persist in mammals, including humans, with profound disruption of rod and cone function. Ongoing experiments are designed to elucidate the phototransduction mechanism, including the identity of the photopigment and the nature of downstream signaling pathways. In other studies, we seek to provide a more detailed characterization of the photic responsiveness and both morphological and functional evidence concerning possible interactions with conventional rod- and cone-driven retinal circuits. These studies are of potential value in understanding and designing appropriate therapies for jet lag, the negative consequences of shift work, and seasonal affective disorder.

Inter-individual variability refers to differences in the expression of behaviors between members of a population. For instance, some individuals take greater risks, are more attracted to immediate gains or are more susceptible to drugs of abuse than others. To probe the neural bases of inter-individual variability  we study reward seeking and decision-making in mice, and dissect the specific role of dopamine in the modulation of these behaviors. Using a spatial version of the multi-armed bandit task, in which mice are faced with consecutive binary choices, we could link modifications of midbrain dopamine cell dynamics with modulation of exploratory behaviors, a major component of individual characteristics in mice. By analyzing mouse behaviors in semi-naturalistic environments, we then explored the role of social relationships in the shaping of dopamine activity and associated beahviors. I will present recent data from the laboratory suggesting that changes in the activity of dopaminergic networks link social influences with variations in the expression of non-social behaviors: by acting on the dopamine system, the social context may indeed affect the capacity of individuals to make decisions, as well as their vulnerability to drugs of abuse, in particular nicotine.

The primary motor cortex (M1) is a major output center for movement execution and motor learning, and its dysfunction contributes to the pathophysiology of Parkinson’s disease (PD). While human studies have indicated that a loss of midbrain dopamine neurons alters M1 activation, the mechanisms underlying this phenomenon remain unclear. Using a mouse model of PD, we uncovered several shifts within M1 circuitry following dopamine depletion, including impaired excitation by thalamocortical afferents and altered excitability. Our findings add to the growing body of literature highlighting M1 as a major contributor in PD, and provide targeted neural substrates for possible therapeutic interventions.

In behaving rodents, CA1 pyramidal neurons receive spatially-tuned depolarizing synaptic input while traversing a specific location within an environment called its place. Midbrain dopamine neurons participate in reinforcement learning, and bursts of action potentials riding a depolarizing wave of synaptic input signal rewards and reward expectation. Interestingly, slice electrophysiology in vitro shows that both types of cells exhibit a pronounced reduction in firing rate (adaptation) and even cessation of firing during sustained depolarization. We included a five state Markov model of NaV1.6 (for CA1) and NaV1.2 (for dopamine neurons) respectively, in computational models of these two types of neurons. Our simulations suggest that long-term inactivation of this channel is responsible for the adaptation in CA1 pyramidal neurons, in response to triangular depolarizing current ramps. We also show that the differential contribution of slow inactivation in two subpopulations of midbrain dopamine neurons can account for their different dynamic ranges, as assessed by their responses to similar depolarizing ramps. These results suggest long-term inactivation of the sodium channel is a general mechanism for adaptation.

Natural soundscapes such as from a forest, a busy restaurant, or a busy intersection are generally composed of a cacophony of sounds that the brain needs to interpret either independently or collectively. In certain instances sounds - such as from moving cars, sirens, and people talking - are perceived in unison and are recognized collectively as single sound (e.g., city noise). In other instances, such as for the cocktail party problem, multiple sounds compete for attention so that the surrounding background noise (e.g., speech babble) interferes with the perception of a single sound source (e.g., a single talker). I will describe results from my lab on the perception and neural representation of auditory textures. Textures, such as a from a babbling brook, restaurant noise, or speech babble are stationary sounds consisting of multiple independent sound sources that can be quantitatively defined by summary statistics of an auditory model (McDermott & Simoncelli 2011). How and where in the auditory system are summary statistics represented and the neural codes that potentially contribute towards their perception, however, are largely unknown. Using high-density multi-channel recordings from the auditory midbrain of unanesthetized rabbits and complementary perceptual studies on human listeners, I will first describe neural and perceptual strategies for encoding and perceiving auditory textures. I will demonstrate how distinct statistics of sounds, including the sound spectrum and high-order statistics related to the temporal and spectral correlation structure of sounds, contribute to texture perception and are reflected in neural activity. Using decoding methods I will then demonstrate how various low and high-order neural response statistics can differentially contribute towards a variety of auditory tasks including texture recognition, discrimination, and categorization. Finally, I will show examples from our recent studies on how high-order sound statistics and accompanying neural activity underlie difficulties for recognizing speech in background noise.

Growing evidence suggests the ventral pallidum (VP) is critical for drug intake and seeking behaviors. Receiving dense projections from the nucleus accumbens as well as dopamine inputs from the midbrain, the VP plays a central role in the control of motivated behaviors. Repeated exposure to cocaine is known to alter VP neuronal firing and neurotransmission. Surprisingly, there is limited information on the molecular adaptations occurring in VP neurons following cocaine intake.To provide insights into cocaine-induced transcriptional alterations we performed RNA-sequencing on VP of mice following cocaine self-administration. Gene Ontology analysis pointed toward alterations in dendrite- and spinerelated genes. Subsequent transcriptional regulator analysis identified the transcription factor Nr4a1 as a common regulator for these sets of morphology-related genes.Consistent with the central role of the VP in reward, its neurons project to several key regions associated with cocaine-mediated behaviors. We thus assessed Nr4a1 expression levels in various projection populations.Following cocaine self-administration, VP neurons projecting to the mediodorsal thalamus (MDT) showed significantly increased Nr4a1 levels. To further investigate the role of Nr4a1 in cocaine intake and relapse, we bidirectionally manipulated its expression levels selectively in VP neurons projecting to the MDT. Increasing Nr4a1 levels resulted in enhanced relapse-like behaviors accompanied by a blockage of cocaine-induced spinogenesis.However, decreasing Nr4a1expression levels completely abolished cocaine intake and consequential relapse-like behaviors. Together, our preliminary findings suggest that drug-induced neuronal remodeling in pallido-thalamic circuits is critical for cocaine intake and relapse-like behaviors.

The serotonin system is the most frequently targeted neural system pharmacologically for treating psychiatric disorders, including depression and anxiety. Serotonin neurons of the dorsal and median raphe nuclei (DR, MR) collectively innervate the entire forebrain and midbrain, modulating diverse physiology and behaviour. By using viral-genetic methods, we found that DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioural functions. To gain a fundamental understanding of the molecular heterogeneity of DR and MR, we used single-cell RNA - sequencing (scRNA-seq) to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters. We generated novel intersectional viral-genetic tools to access specific subpopulations. Whole-brain axonal projection mapping revealed that the molecular features of these distinct serotonin groups reflect their anatomical organization and provide tools for future exploration of the full projection map of molecularly defined serotonin groups. The molecular architecture of serotonin system lays the foundation for integrating anatomical, neurochemical, physiological, and behavioural functions.

Animals are motivated to acquire knowledge. A particularly striking example is information seeking behavior: animals often seek out sensory cues that will inform them about the properties of uncertain future rewards, even when there is no way for them to use this information to influence the reward outcome, and even when this information comes at a considerable cost. Evidence from monkey electrophysiology and human fMRI studies suggests that orbitofrontal cortex and midbrain dopamine neurons represent the subjective value of knowledge during information seeking behavior. However, it remains unclear how the brain assigns value to information and how it integrates this with other incentives to drive behavior. We have therefore developed a task to test if information preferences are present in mice and study how informational value is imparted on stimuli. Mice are trained to enter a center port and receive an initial odor that instructs them to either go to an informative side port, go to an uninformative side port, or choose freely between them. The chosen side port then yields a second odor cue followed by a delayed probabilistic water reward. The informative port’s odor cue indicates whether the upcoming reward will be big or small. The uninformative port’s odor cue is uncorrelated with the trial outcome. Crucially, the two ports only differ in their odor cues, not in their water value since both offer identical probabilities of big and small rewards. We find that mice prefer the informative port. This preference is evident as a higher percentage choice of the informative port when given a free choice (67% +/- 1.7%, n = 14, p < 0.03), as well as by faster reaction times when instructed to go to the informative port (544ms +/- 21ms vs 795ms +/- 21ms, n = 14, p < 0.001). The preference for information is robust to within-animal reversals of informative and uninformative port locations, and, moreover, mice are willing to pay for information by choosing the informative port even if its reward amount is reduced to be substantially lower than the uninformative port. These behavioral observations suggest that odor stimuli are imparted with informational value as mice learn the information seeking task. We are currently imaging neural activity in orbitofrontal cortex with microendoscopes to identify changes in neural activity that may reflect value associated with the acquisition of knowledge.