Motivational Impairment is Accompanied by Corticoaccumbal Dysfunction in the BACHD-Tg5 Rat Model of Huntington's Disease.

Neuropsychiatric symptoms, such as avolition, apathy, and anhedonia, precede the onset of debilitating motor symptoms in Huntington's disease (HD), and their development may give insight into early disease progression and treatment. However, the neuronal and circuit mechanisms of premanifest HD pathophysiology are not well-understood. Here, using a transgenic rat model expressing the full-length human mutant HD gene, we find early and profound deficits in reward motivation in the absence of gross motor abnormalities. These deficits are accompanied by significant and progressive dysfunction in corticostriatal processing and communication among brain areas critical for reward-driven behavior. Together, our results define early corticostriatal dysfunction as a possible pathogenic contributor to psychiatric disturbances and may help identify potential pharmacotherapeutic targets for the treatment of HD.

Delta-9-tetrahydrocannabinol potentiates fear memory salience through functional modulation of mesolimbic dopaminergic activity states.

Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and preclinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally subthreshold fear conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurones whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurones. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission.

Inter-individual differences in the impulsive/compulsive dimension: deciphering related dopaminergic and serotonergic metabolisms at rest.

Several impulse control disorders such as ADHD, mania, personality disorders or substance abuse share common behavioural traits, like impulsiveness, risk-taking or inflexible behaviour. These disorders are treated with drugs targeting dopamine (DA) and/or serotonin (5-HT). However, the patient's monoamine imbalance that these neurotransmitters compensate is unclear. This study aims to investigate the patterns of DA and 5-HT metabolisms at rest within selected brain regions related to inter-individual variability in six main components of impulsivity/compulsivity (anticipatory hyperactivity, premature responses, delay discounting, risk-taking, perseveration, flexibility). Rats with adaptive and highly inadaptive behaviours were identified in each task and a sensitive biochemical approach allowed mapping of post-mortem endogenous monoamine tissue content in 20 brain areas. Distinct patterns of 5-HT and DA metabolisms were revealed according to the behavioural traits. Except for hyperactive responses, lower control of actions was mainly associated with a lower DA or 5-HT metabolism in prefrontal and/or subcortical areas (i.e. in orbitofrontal cortex (DA), amygdala and anterior cingulate cortex (5-HT) for inflexible and risk-prone rats). Our results reveal the complex nature of behavioural traits related to impulse control disorders through their associated monoaminergic networks at rest, paving the way for understanding the link between mental disorders and drug therapeutic actions.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.

Inter-individual differences in decision-making, flexible and goal-directed behaviors: novel insights within the prefronto-striatal networks.

Inflexible behavior is a hallmark of several decision-making-related disorders such as ADHD and addiction. As in humans, a subset of healthy rats makes poor decisions and prefers immediate larger rewards despite suffering large losses in a rat gambling task (RGT). They also display a combination of traits reminiscent of addiction, notably inflexible behavior and perseverative responses. The goal of the present work was twofold: (1) to elucidate if behavioral inflexibility of poor decision-makers could be related to a lower quality of goal-directed behavior (action-outcome associations); (2) to uncover the neural basis of inter-individual differences in goal-directed behavior. We specifically assessed inter-individual differences in decision-making in the RGT, flexibility in the RGT-reversed version and goal-directed behavior in a contingency degradation test, i.e., response adaptation when dissociating reward delivery from the animal's action. The contributions of the medial prefrontal cortex and the dorsal striatum to action-outcome associations were assessed using Zif268 immunodetection. Inflexible behavior was related to a lower sensitivity to contingency degradation in all poor decision-makers and only in a few good decision-makers. This poorer sensitivity was associated with a lower immunoreactivity in prelimbic and infralimbic cortices and a higher one in the dorsomedial and dorsolateral striatum. These findings suggest that an imbalanced prefronto-striatal activity could underlie inaccurate goal representation in changing environments and may promote maladaptive habit formation among poor decision-makers. These data strengthen our previous work identifying biomarkers of vulnerability to develop psychiatric disorders and demonstrate the relevance of inter-individual differences to model maladaptive behaviors.

Correlative analysis of dopaminergic and serotonergic metabolism across the brain to study monoaminergic function and interaction.

BACKGROUND: The widespread innervation of dopamine (DA) and serotonin (5-HT) systems in cortical and subcortical regions suggests that their biochemical interactions can occur in multiple regions directly or indirectly via neurobiological networks. NEW METHOD: The present study was aimed at validating a neurochemical approach of monoaminergic function based on inter-individual variability of monoamine tissue contents in various cortical and subcortical areas. We focused on monoamines metabolism and examined correlations within and between these monoaminergic systems in selected regions for the metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and/or homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) alone or with respect to the turnover indexes DOPAC/DA, DOPAC+HVA/DA and 5-HIAA/5-HT. RESULTS: The tissue content of metabolites and their parent drug correlated within a brain region. Conversely, a few specific relationships (10%) were observed for each turnover in paired brain regions and even less between the 5-HT and DA turnovers. The number of correlations was lower when looking at the metabolite tissue contents. In all cases, the 5-HT and DA turnover indexes or metabolites correlated positively within a brain region. COMPARISON WITH EXISTING METHOD(S): These data validate the inter-individual analysis of monoamine tissue content by providing evidence that the metabolite correlates with the parent neurotransmitter in the same region. The pattern of correlations of metabolisms reported here differs from that of the parent neurotransmitters, notably regarding the relationships of DA turnovers between striatal territories. CONCLUSION: The whole neurochemical approach is of interest for characterizing monoaminergic systems interaction in various genetic or pharmacological models of neuropsychiatric diseases.

Prefronto-subcortical imbalance characterizes poor decision-making: neurochemical and neural functional evidences in rats.

A major challenge of decision-making research in recent years has been to develop models of poor decision-making to identify its neural bases. Toward this goal, we developed a Rat Gambling Task that discerns good and poor decision-makers in a complex and conflicting situation such as the human Iowa Gambling Task. Nothing is known about the role of the monoaminergic modulatory systems in shaping these phenotypes. Moreover, functional and temporal contributions of brain areas during poor compared to good decision-making remains elusive. Good and poor decision-makers were identified in the Rat Gambling Task. We investigated neurobiological correlates of decision-making capacities in (1) dopamine and serotonin turnovers using post-mortem tissue measurements, (2) the neural circuits differentially recruited during decision-making within the prefronto-subcortical network using cellular Fos immunodetection. Imbalance in monoamine metabolism was revealed in poor decision-makers, i.e. a higher infralimbic vs. lower amygdala serotonergic metabolism. Moreover, good decision-making recruited a wide prefronto-subcortical network but once good choices had been made, a disengagement of key prefrontal areas (insular and infralimbic cortices notably) and the amygdala was observed. By contrast, poor decision-making was associated with a strikingly low recruitment of the prefronto-subcortical network, together with sustained amygdala activity. Our results identify two complementary neurobiological substrates characterizing poor decision-makers: imbalanced monoaminergic systems at rest, congruent with their previously identified complex behavioral phenotype, and an aberrant low recruitment of key brain areas for executive functions and affective valence during the process of decision-making. These biomarkers could sustain vulnerability to developing poor decision-making related disorders.

Tales from the dark side: do neuromodulators of drug withdrawal require changes in endocannabinoid tone?

Environmental and interoceptive cues are theorized to serve as 'signals' that motivate drug seeking and effects that may be augmented in the withdrawn state. Phasic dopamine release events are observed in the nucleus accumbens in response to such motivational salient stimuli and are thought to be necessary for drug-associated cues to trigger craving. We recently demonstrated how dopamine neurons encode stimuli conditioned to a negative event, as might occur during conditioned withdrawal, and stimuli predicting the avoidance of negative events, as might occur as an addict seeks out drugs to prevent withdrawal. In this review we first discuss how the subsecond dopamine release events might process conditioned withdrawal and drug seeking driven by negative reinforcement processes within the context of our dopamine data obtained during conditioned avoidance procedures. We next describe how the endocannabinoid system modulates phasic dopamine release events and how it might be harnessed to treat negative affective states in addiction. Specifically, we have demonstrated that endocannabinoids in the ventral tegmentum sculpt cue-induced accumbal surges in dopamine release and, therefore, may also be mobilized during drug withdrawal.

Cannabinoid receptor activation shifts temporally engendered patterns of dopamine release.

The ability to discern temporally pertinent environmental events is essential for the generation of adaptive behavior in conventional tasks, and our overall survival. Cannabinoids are thought to disrupt temporally controlled behaviors by interfering with dedicated brain timing networks. Cannabinoids also increase dopamine release within the mesolimbic system, a neural pathway generally implicated in timing behavior. Timing can be assessed using fixed-interval (FI) schedules, which reinforce behavior on the basis of time. To date, it remains unknown how cannabinoids modulate dopamine release when responding under FI conditions, and for that matter, how subsecond dopamine release is related to time in these tasks. In the present study, we hypothesized that cannabinoids would accelerate timing behavior in an FI task while concurrently augmenting a temporally relevant pattern of dopamine release. To assess this possibility, we measured subsecond dopamine concentrations in the nucleus accumbens while mice responded for food under the influence of the cannabinoid agonist WIN 55,212-2 in an FI task. Our data reveal that accumbal dopamine concentrations decrease proportionally to interval duration--suggesting that dopamine encodes time in FI tasks. We further demonstrate that WIN 55,212-2 dose-dependently increases dopamine release and accelerates a temporal behavioral response pattern in a CB1 receptor-dependent manner--suggesting that cannabinoid receptor activation modifies timing behavior, in part, by augmenting time-engendered patterns of dopamine release. Additional investigation uncovered a specific role for endogenous cannabinoid tone in timing behavior, as elevations in 2-arachidonoylglycerol, but not anandamide, significantly accelerated the temporal response pattern in a manner akin to WIN 55,212-2.

Rodent versions of the iowa gambling task: opportunities and challenges for the understanding of decision-making.

Impaired decision-making is a core problem in several psychiatric disorders including attention-deficit/hyperactivity disorder, schizophrenia, obsessive-compulsive disorder, mania, drug addiction, eating disorders, and substance abuse as well as in chronic pain. To ensure progress in the understanding of the neuropathophysiology of these disorders, animal models with good construct and predictive validity are indispensable. Many human studies aimed at measuring decision-making capacities use the Iowa gambling task (IGT), a task designed to model everyday life choices through a conflict between immediate gratification and long-term outcomes. Recently, new rodent models based on the same principle have been developed to investigate the neurobiological mechanisms underlying IGT-like decision-making on behavioral, neural, and pharmacological levels. The comparative strengths, as well as the similarities and differences between these paradigms are discussed. The contribution of these models to elucidate the neurobehavioral factors that lead to poor decision-making and to the development of better treatments for psychiatric illness is considered, along with important future directions and potential limitations.

Inter-individual decision-making differences in the effects of cingulate, orbitofrontal, and prelimbic cortex lesions in a rat gambling task.

Deficits in decision-making is a hallmark of several neuropsychiatric pathologies but is also observed in some healthy individuals that could be at risk to develop these pathologies. Poor decision-making can be revealed experimentally in humans using the Iowa gambling task, through the inability to select options that ensure long term gains over larger immediate gratification. We devised an analogous task in the rat, based on uncertainty and conflicting choices, the rat gambling task (RGT). It similarly reveals good and poor performers within a single session. Using this task, we investigated the role of three prefrontal cortical areas, the orbitofrontal, prelimbic, and cingulate cortices on decision-making, taking into account inter-individual variability in behavioral performances. Here, we show that these three distinct subregions are differentially engaged to solve the RGT. Cingulate cortex lesion mainly delayed good decision-making whereas prelimbic and orbitofrontal cortices induced different patterns of inadapted behaviors in the task, indicating varying degree of functional specialization of these three areas. Their contribution largely depended on the level of adaptability demonstrated by each individual to the constraint of the task. The inter-individual differences in the effect of prefrontal cortex area lesions on decision-making revealed in this study open new perspectives in the search for vulnerability markers to develop disorders related to executive dysfunctioning.