Thirst recruits phasic dopamine signaling through subfornical organ neurons.

Thirst is a highly potent drive that motivates organisms to seek out and consume balance-restoring stimuli. The detection of dehydration is well understood and involves signals of peripheral origin and the sampling of internal milieu by first order homeostatic neurons within the lamina terminalis-particularly glutamatergic neurons of the subfornical organ expressing CaMKIIa (SFOCaMKIIa). However, it remains unknown whether mesolimbic dopamine pathways that are critical for motivation and reinforcement integrate information from these "early" dehydration signals. We used in vivo fiber photometry in the ventral tegmental area and measured phasic dopamine responses to a water-predictive cue. Thirst, but not hunger, potentiated the phasic dopamine response to the water cue. In euvolemic rats, the dipsogenic hormone angiotensin II, but not the orexigenic hormone ghrelin, potentiated the dopamine response similarly to that observed in water-deprived rats. Chemogenetic manipulations of SFOCaMKIIa revealed bidirectional control of phasic dopamine signaling during cued water reward. Taking advantage of within-subject designs, we found predictive relationships between changes in cue-evoked dopamine response and changes in behavioral responses-supporting a role for dopamine in motivation induced by homeostatic need. Collectively, we reveal a putative mechanism for the invigoration of goal-directed behavior: internal milieu communicates to first order, need state-selective circuits to potentiate the mesolimbic dopamine system's response to cues predictive of restorative stimuli.

Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli.

Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e., hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS-). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS-, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. Cues that predict food availability powerfully regulate food-seeking behavior. Here we show that cue-evoked changes in both nucleus accumbens (NAc) dopamine (DA) and NAc cell activity are modulated by intra-cranial infusions of the stomach hormone ghrelin--a hormone known to act centrally to promote food intake. These data demonstrate that hormones associated with physiological state (i.e., hunger) can affect encoding of food-predictive cues in brain regions that drive food-motivated behavior.

Linking neuroscience with modern concepts of impulse control disorders in Parkinson's disease.

Patients with Parkinson's disease (PD) may experience impulse control disorders (ICDs) when on dopamine agonist therapy for their motor symptoms. In the last few years, a rapid growth of interest for the recognition of these aberrant behaviors and their neurobiological correlates has occurred. Recent advances in neuroimaging are helping to identify the neuroanatomical networks responsible for these ICDs, and together with psychopharmacological assessments are providing new insights into the brain status of impulsive behavior. The genetic associations that may be unique to ICDs in PD are also being identified. Complementing human studies, electrophysiological and biochemical studies in animal models are providing insights into neuropathological mechanisms associated with these disorders. New animal models of ICDs in PD patients are being implemented that should provide critical means to identify efficacious therapies for PD-related motor deficits while avoiding ICD side effects. Here, we provide an overview of these recent advances, with a particular emphasis on the neurobiological correlates reported in animal models and patients along with their genetic underpinnings.

Nucleus accumbens responses differentiate execution and restraint in reward-directed behavior.

Our behavior is powerfully driven by environmental cues that signal the availability of rewarding stimuli. We frequently encounter stimuli-a bowl of candy or an alert from our smartphone-that trigger actions to obtain those rewards, even though there may be positive outcomes associated with not acting. The inability to restrain one's action in the presence of reward-associated cues is one type of impulsive behavior and a component of such maladaptive behaviors as overeating, gambling, and substance abuse. The nucleus accumbens (NAc) is ideally situated to integrate multiple cognitive and affective inputs to bias action via outputs through the basal ganglia. NAc neurons have been shown to respond to cues that predict reward availability, goal-directed behaviors aimed at obtaining them, and delivery of the reward itself. As these processes are typically associated, it is difficult to discern whether signals in the NAc are more closely related to processing reward-predictive aspects of goal-directed behavior or selection of behavioral response. To dissociate these possibilities, we recorded the activity of NAc neurons while rats performed a task in which two different cues both informed rats of reward availability but required them to either press a lever (Go) or withhold pressing (NoGo) to obtain the reward. Individual cue-responsive neurons showed either increases or decreases in activity at cue onset. Increases in activity were larger, and decreases smaller, when rats withheld lever pressing, whether correctly for NoGo trials or in error on Go trials. Thus NAc cue responses correlated with action, regardless of cue type or accuracy.

Chronic water restriction reduces sensitivity to brain stimulation reward in male and female rats.

States of physiological need motivate individuals to seek and consume stimuli that restore homeostatic balance. This goal-directed behavior is driven, in part, by pathways that process reward and are sensitive to changes in physiological state, including the mesolimbic dopamine system. The effects of hunger and its physiological markers have been more widely studied for their role in modulating reward signaling pathways. However, fluid need produces robust goal-directed behavior and has also been shown to affect neural substrates of reward processing. To test how acute and chronic states of thirst might alter reward sensitivity, we used the intracranial self-stimulation (ICSS) rate-frequency paradigm (Carlezon & Chartoff, 2007) with male and female Long Evans rats. We hypothesized that sensitivity to ICSS would increase under an acute need state for water and would decrease under chronic deprivation. We found that acute water deprivation for 22-hours prior to the ICSS session did not alter any parameters of reward sensitivity. To elicit motivated behavior toward water in the absence of physiological need, we chemogenetically activated glutamatergic neurons of the subfornical organ (SFO). Despite eliciting more water consumption than acute deprivation, acute chemogenetic activation of SFO neurons also did not alter reward sensitivity. Finally, subjects underwent a five-day chronic water restriction protocol with daily ICSS sessions to determine the effects of sustained physiological need. Chronic water restriction resulted in reduced sensitivity to ICSS. Together, these results indicate that persistent changes in physiological state alter the responsiveness of reward circuitry that could potentially exacerbate maladaptive reward-seeking behaviors.

Nucleus accumbens shell, but not core, tracks motivational value of salt.

To appropriately respond to an affective stimulus, we must be able to track its value across changes in both the external and internal environment. The nucleus accumbens (NAc) is a critical component of reward circuitry, but recent work suggests that the NAc encodes aversion as well as reward. It remains unknown whether differential NAc activity reflects flexible changes in stimulus value when it is altered due to a change in physiological state. We measured the activity of individual NAc neurons when rats were given intraoral infusions of a hypertonic salt solution (0.45 M NaCl) across multiple sessions in which motivational state was manipulated. This normally nonpreferred taste was made rewarding via sodium depletion, which resulted in a strong motivation to seek out and consume salt. Recordings were made in three conditions: while sodium replete (REP), during acute sodium depletion (DEP), and following replenishment of salt to normal sodium balance (POST). We found that NAc neurons in the shell and core subregions responded differently across the three conditions. In the shell, we observed overall increases in NAc activity when the salt solution was nonpreferred (REP) but decreases when the salt solution was preferred (DEP). In the core, overall activity was significantly altered only after sodium balance was restored (POST). The results lend further support to the selective encoding of affective stimuli by the NAc and suggest that NAc shell is particularly involved in flexibly encoding stimulus value based on motivational state.

Hedonic and nucleus accumbens neural responses to a natural reward are regulated by aversive conditioning.

The nucleus accumbens (NAc) plays a role in hedonic reactivity to taste stimuli. Learning can alter the hedonic valence of a given stimulus, and it remains unclear how the NAc encodes this shift. The present study examined whether the population response of NAc neurons to a taste stimulus is plastic using a conditioned taste aversion (CTA) paradigm. Electrophysiological and electromyographic (EMG) responses to intraoral infusions of a sucrose (0.3 M) solution were made in naïve rats (Day 1). Immediately following the session, half of the rats (n = 6; Paired) received an injection of lithium chloride (0.15 M; i.p.) to induce malaise and establish a CTA while the other half (n = 6; Unpaired) received a saline injection. Days later (Day 5), NAc recordings during infusions of sucrose were again made. Electrophysiological and EMG responses to sucrose did not differ between groups on Day 1. For both groups, the majority of sucrose responsive neurons exhibited a decrease in firing rate (77% and 71% for Paired and Unpaired, respectively). Following conditioning, in Paired rats, EMG responses were indicative of aversion. Moreover, the majority of responsive NAc neurons now exhibited an increase in firing rate (69%). Responses in Unpaired rats were unchanged by the experience. Thus, the NAc differentially encodes the hedonic value of the same stimulus based on learned associations.

Risk-preference differentiates orbitofrontal cortex responses to freely chosen reward outcomes.

To successfully evaluate potential courses of action and choose the most favorable, we must consider the outcomes that may result. Many choices involve risk, our assessment of which may lead us to success or failure in matters financial, legal or health-related. The orbitofrontal cortex (OFC) has been implicated as critical for evaluating choices based on risk. To measure how outcomes of risky decisions are represented in the OFC, we recorded the electrophysiological activity of single neurons while rats made behavioral responses to obtain rewards under conditions of either certainty or risk. Rats exhibited different risk-preferences when given the opportunity to choose. In risk-preferring rats, OFC responses were enhanced following the delivery of large rewards obtained under risk compared with smaller, certain rewards and reward omission. However, in risk-neutral rats, neurons showed similarly enhanced responses to both large rewards obtained under risk and smaller, certain rewards compared with reward omission. Thus, the responses of OFC neurons reflected the subjective evaluation of outcomes in individuals with different risk-preferences. Such enhanced neural responding to risky rewards may serve to bias individuals towards risk-preference in decision-making.

Monotonic coding of numerosity in macaque lateral intraparietal area.

As any child knows, the first step in counting is summing up individual elements, yet the brain mechanisms responsible for this process remain obscure. Here we show, for the first time, that a population of neurons in the lateral intraparietal area of monkeys encodes the total number of elements within their classical receptive fields in a graded fashion, across a wide range of numerical values (2-32). Moreover, modulation of neuronal activity by visual quantity developed rapidly, within 100 ms of stimulus onset, and was independent of attention, reward expectations, or stimulus attributes such as size, density, or color. The responses of these neurons resemble the outputs of "accumulator neurons" postulated in computational models of number processing. Numerical accumulator neurons may provide inputs to neurons encoding specific cardinal values, such as "4," that have been described in previous work. Our findings may explain the frequent association of visuospatial and numerical deficits following damage to parietal cortex in humans.

Effects of chronic cannabinoid exposure during adolescence on reward preference and mPFC activation in adulthood.

Cannabis is one of the most commonly used drugs among adolescents, with initial use beginning between the ages of 12 to 17. Although often perceived as a 'soft drug', both short- and long-term use have been associated with numerous adverse outcomes, including cognitive impairment, increased risk of substance abuse, and heightened risk of psychosis or schizophrenia in individuals with a predisposition. Further, the severity of these impairments is closely linked to initiation of use, i.e. earlier use increases risk. It has been suggested that adolescent vulnerability to the adverse consequences of cannabis use is due to ongoing brain development occurring during this time. Indeed, the adolescent brain continues to be remodeled well into adolescence and early adulthood, particularly in the prefrontal cortex (PFC). The medial prefrontal cortex (mPFC) has been implicated in reward processing and decision-making and alterations in mPFC development due to adolescent cannabis exposure could impair these functions. To model the effects of cannabis on mPFC function, we administered the synthetic cannabinoid WIN 55, 212-2 (WIN) to male and female rats from postnatal day 30-60. Once animals reached adulthood, we used a Probabilistic Reward (PR) choice task to elicit PFC activity and measure how patterns of activity to task-related events were modulated by adolescent WIN-treatment. Adult animals showed subtle effects of WIN-treatment on choice patterns. During task performance, mPFC activity elicited by lever press at the time of choices and reward delivery following choices were reduced in WIN-treated animals. This lasting effect of WIN suggests an impairment of the maturation of excitatory-inhibitory balance of signals in mPFC during adolescence, which may alter executive function into adulthood.

Nonverbal representation of time and number in adults.

A wealth of human and animal research supports common neural processing of numerical and temporal information. Here we test whether adult humans spontaneously encode number and time in a paradigm similar to those previously used to test the mode-control model in animals. Subjects were trained to classify visual stimuli that varied in both number and duration as few/short or many/long. Subsequently subjects were tested with novel stimuli that varied time and held number constant (eight flashes in 0.8-3.2s) or varied number and held time constant (4-16 flashes in 1.6s). Adult humans classified novel stimuli as many/long as monotonic functions of both number and duration, consistent with simultaneous, nonverbal, analog encoding. Numerical sensitivity, however, was finer than temporal sensitivity, suggesting differential salience of time and number. These results support the notion that adults simultaneously represent the number and duration of stimuli but suggest a possible asymmetry in their representations.

Brain Stimulation Reward Supports More Consistent and Accurate Rodent Decision-Making than Food Reward.

Animal models of decision-making rely on an animal's motivation to decide and its ability to detect differences among various alternatives. Food reinforcement, although commonly used, is associated with problematic confounds, especially satiety. Here, we examined the use of brain stimulation reward (BSR) as an alternative reinforcer in rodent models of decision-making and compared it with the effectiveness of sugar pellets. The discriminability of various BSR frequencies was compared to differing numbers of sugar pellets in separate free-choice tasks. We found that BSR was more discriminable and motivated greater task engagement and more consistent preference for the larger reward. We then investigated whether rats prefer BSR of varying frequencies over sugar pellets. We found that animals showed either a clear preference for sugar reward or no preference between reward modalities, depending on the frequency of the BSR alternative and the size of the sugar reward. Overall, these results suggest that BSR is an effective reinforcer in rodent decision-making tasks, removing food-related confounds and resulting in more accurate, consistent, and reliable metrics of choice.

Acute and long-term effects of adolescent methylphenidate on decision-making and dopamine receptor mRNA expression in the orbitofrontal cortex.

Though commonly used as a treatment for ADHD, the psychostimulant methylphenidate (MPH) is also misused and abused in adolescence in both clinical and general populations. Although MPH acts via pathways activated by other drugs of abuse, the short- and long-term effects of MPH on reward processing in learning and decision-making are not clearly understood. We examined the effect of adolescent MPH treatment on a battery of reward-directed behaviors both in adolescence during its administration and in adulthood after its discontinuation. We further measured whether MPH had lasting effects on dopamine receptor mRNA expression in orbitofrontal cortex (OFC) that may correspond with behavior. Long-Evans rats were injected with MPH (0, 1, 2.5, or 5mg/kg IP) twice daily from middle to late adolescence (PD38-57). During adolescence, the high dose of MPH reduced preference for large rewards in a Reward Magnitude Discrimination task, but did not affect preference for smaller-sooner rewards in a Delay Discounting task. In adulthood, after discontinuation of MPH, animals previously treated with the moderate dose of MPH showed improved acquisition, but not reversal, in a Reversal Learning task. MPH exposure did not increase preference for large-risky rewards in a Risk task in adulthood. We then quantified mRNA expression of D1, D2, and D3 receptors in the OFC using qPCR. MPH increased mRNA expression of dopamine D3 receptor subtype, but not D1 or D2. Overall, these results indicate that MPH has both immediate and lasting effects on reward-dependent learning and decisions, as well as dopaminergic function in rodents.

Response of neurons in the lateral intraparietal area during a combined visual discrimination reaction time task.

Decisions about the visual world can take time to form, especially when information is unreliable. We studied the neural correlate of gradual decision formation by recording activity from the lateral intraparietal cortex (area LIP) of rhesus monkeys during a combined motion-discrimination reaction-time task. Monkeys reported the direction of random-dot motion by making an eye movement to one of two peripheral choice targets, one of which was within the response field of the neuron. We varied the difficulty of the task and measured both the accuracy of direction discrimination and the time required to reach a decision. Both the accuracy and speed of decisions increased as a function of motion strength. During the period of decision formation, the epoch between onset of visual motion and the initiation of the eye movement response, LIP neurons underwent ramp-like changes in their discharge rate that predicted the monkey's decision. A steeper rise in spike rate was associated with stronger stimulus motion and shorter reaction times. The observations suggest that neurons in LIP integrate time-varying signals that originate in the extrastriate visual cortex, accumulating evidence for or against a specific behavioral response. A threshold level of LIP activity appears to mark the completion of the decision process and to govern the tradeoff between accuracy and speed of perception.

Effects of voluntary alcohol intake on risk preference and behavioral flexibility during rat adolescence.

Alcohol use is common in adolescence, with a large portion of intake occurring during episodes of binging. This pattern of alcohol consumption coincides with a critical period for neurocognitive development and may impact decision-making and reward processing. Prior studies have demonstrated alterations in adult decision-making following adolescent usage, but it remains to be seen if these alterations exist in adolescence, or are latent until adulthood. Here, using a translational model of voluntary binge alcohol consumption in adolescents, we assess the impact of alcohol intake on risk preference and behavioral flexibility during adolescence. During adolescence (postnatal day 30-50), rats were given 1-hour access to either a 10% alcohol gelatin mixture (EtOH) or a calorie equivalent gelatin (Control) at the onset of the dark cycle. EtOH consuming rats were classified as either High or Low consumers based on intake levels. Adolescent rats underwent behavioral testing once a day, with one group performing a risk preference task, and a second group performing a reversal-learning task during the 20-day period of gelatin access. EtOH-High rats showed increases in risk preference compared to Control rats, but not EtOH-Low animals. However, adolescent rats did a poor job of matching their behavior to optimize outcomes, suggesting that adolescents may adopt a response bias. In addition, adolescent ethanol exposure did not affect the animals' ability to flexibly adapt behavior to changing reward contingencies during reversal learning. These data support the view that adolescent alcohol consumption can have short-term detrimental effects on risk-taking when examined during adolescence, which does not seem to be attributable to an inability to flexibly encode reward contingencies on behavioral responses.

Representation of numerosity in posterior parietal cortex.

Humans and animals appear to share a similar representation of number as an analog magnitude on an internal, subjective scale. Neurological and neurophysiological data suggest that posterior parietal cortex (PPC) is a critical component of the circuits that form the basis of numerical abilities in humans. Patients with parietal lesions are impaired in their ability to access the deep meaning of numbers. Acalculiac patients with inferior parietal damage often have difficulty performing arithmetic (2 + 4?) or number bisection (what is between 3 and 5?) tasks, but are able to recite multiplication tables and read or write numerals. Functional imaging studies of neurologically intact humans performing subtraction, number comparison, and non-verbal magnitude comparison tasks show activity in areas within the intraparietal sulcus (IPS). Taken together, clinical cases and imaging studies support a critical role for parietal cortex in the mental manipulation of numerical quantities. Further, responses of single PPC neurons in non-human primates are sensitive to the numerosity of visual stimuli independent of low-level stimulus qualities. When monkeys are trained to make explicit judgments about the numerical value of such stimuli, PPC neurons encode their cardinal numerical value; without such training PPC neurons appear to encode numerical magnitude in an analog fashion. Here we suggest that the spatial and integrative properties of PPC neurons contribute to their critical role in numerical cognition.

Olanzapine, but not fluoxetine, treatment increases survival in activity-based anorexia in mice.

Anorexia nervosa (AN) is an eating disorder characterized by extreme hypophagia, hyperactivity, and fear of weight gain. No approved pharmacological treatments exist for AN despite high mortality rates. The activity-based anorexia (ABA) phenomenon models aspects of AN in rodents, including progressive weight loss, reduced food intake, and hyperactivity. First, we optimized the ABA paradigm for mice. We compared mouse strains (Balb/cJ, A/J) for susceptibility with ABA, and evaluated the effects of different food access durations (2, 4, 6, 8, and 10 h) on ABA parameters. Balb/cJ mice exhibited significantly shorter survival time (days until 25% bodyweight loss) in the ABA paradigm compared with A/J mice. Furthermore, 6 h of food access reduced survival in mice housed with wheels without reducing survival in mice housed without wheels. We then evaluated the effects of chronic treatment with fluoxetine (4 weeks) or subchronic treatment with olanzapine (OLZ) (1 week) on ABA in BALB/cJ mice. OLZ (12 mg/kg/day) significantly increased survival and reduced food anticipatory activity (FAA). However, OLZ did not alter food intake or running wheel activity during ad-lib feeding (baseline) or restriction conditions, or in mice housed without wheels. Fluoxetine (18 mg/kg/day) increased food intake and reduced FAA, but did not alter survival. Here, we report for the first time that OLZ, but not fluoxetine, reduces ABA in mice. Our findings indicate further need for clinical investigations into the effects of OLZ, but not selective serotonin reuptake inhibitors, on core features of AN.

One-dimensional dynamics of attention and decision making in LIP.

Where we allocate our visual spatial attention depends upon a continual competition between internally generated goals and external distractions. Recently it was shown that single neurons in the macaque lateral intraparietal area (LIP) can predict the amount of time a distractor can shift the locus of spatial attention away from a goal. We propose that this remarkable dynamical correspondence between single neurons and attention can be explained by a network model in which generically high-dimensional firing-rate vectors rapidly decay to a single mode. We find direct experimental evidence for this model, not only in the original attentional task, but also in a very different task involving perceptual decision making. These results confirm a theoretical prediction that slowly varying activity patterns are proportional to spontaneous activity, pose constraints on models of persistent activity, and suggest a network mechanism for the emergence of robust behavioral timing from heterogeneous neuronal populations.

A role for neural integrators in perceptual decision making.

Decisions based on uncertain information may benefit from an accumulation of information over time. We asked whether such an accumulation process may underlie decisions about the direction of motion in a random dot kinetogram. To address this question we developed a computational model of the decision process using ensembles of neurons whose spiking activity mimics neurons recorded in the extrastriate visual cortex (area MT or V5) and a sensorimotor association area of the parietal lobe (area LIP). The model instantiates the hypothesis that neurons in sensorimotor association areas compute the time integral of sensory signals from the visual cortex, construed as evidence for or against a proposition, and that the decision is made when the integrated evidence reaches a threshold. The model explains a variety of behavioral and physiological measurements obtained from monkeys.