'The risks of playing it safe': a prospective longitudinal study of response to reward in the adolescent offspring of depressed parents

BACKGROUND Alterations in reward processing may represent an early vulnerability factor for the development of depressive disorder. Depression in adults is associated with reward hyposensitivity and diminished reward seeking may also be a feature of depression in children and adolescents. We examined the role of reward responding in predicting depressive symptoms, functional impairment and new-onset depressive disorder over time in the adolescent offspring of depressed parents. In addition, we examined group differences in reward responding between currently depressed adolescents, psychiatric and healthy controls, and also cross-sectional associations between reward responding and measures of positive social/environmental functioning. Method We conducted a 1-year longitudinal study of adolescents at familial risk for depression (n = 197; age range 10-18 years). Reward responding and self-reported social/environmental functioning were assessed at baseline. Clinical interviews determined diagnostic status at baseline and at follow-up. Reports of depressive symptoms and functional impairment were also obtained. RESULTS Low reward seeking predicted depressive symptoms and new-onset depressive disorder at the 1-year follow-up in individuals free from depressive disorder at baseline, independently of baseline depressive symptoms. Reduced reward seeking also predicted functional impairment. Adolescents with current depressive disorder were less reward seeking (i.e. bet less at favourable odds) than adolescents free from psychopathology and those with externalizing disorders. Reward seeking showed positive associations with social and environmental functioning (extra-curricular activities, humour, friendships) and was negatively associated with anhedonia. There were no group differences in impulsivity, decision making or psychomotor slowing. CONCLUSIONS Reward seeking predicts depression severity and onset in adolescents at elevated risk of depression. Adaptive reward responses may be amenable to change through modification of existing preventive psychological interventions

Pain-avoidance versus reward-seeking: an experimental investigation

According to fear-avoidance models, a catastrophic interpretation of a painful experience may give rise to pain-related fear and avoidance, leading to the development and maintenance of chronic pain problems in the long term. However, little is known about how exactly motivation and goal prioritization play a role in the development of pain-related fear. This study investigates these processes in healthy volunteers using an experimental context with multiple, competing goals. In a differential human fear-conditioning paradigm, 57 participants performed joystick movements. In the control condition, one movement (conditioned stimulus; CS+) was followed by a painful electrocutaneous unconditioned stimulus (pain-US) in 50% of the trials, whereas another movement (nonreinforced conditioned stimulus; CS-) was not. In the experimental condition, a reward in the form of lottery tickets (reward-US) accompanied the presentation of the pain-US. Participants were classified into 3 groups, as a function of the goal, they reported to be the most important: (1) pain-avoidance, (2) reward-seeking, and (3) both goals being equally important. Results indicated that neither the reward co-occurring with pain nor the prioritized goal modulated pain-related fear. However, during subsequent choice trials, participants selected the painful movement more often when the reward was presented compared with the context in which the reward was absent. The latter effect was dependent on goal prioritization, with more frequent selections in the reward-seeking group, and the least selections in the pain-avoidance group. Taken together, these results underscore the importance of competing goals and goal prioritization in the attenuation of avoidance behavior

Conditioned-stimulus-elicited emotion and outcome expectation have dissociable effects on reward seeking, and are differentially affected by personality: implications for addiction

A better understanding of the psychological mechanisms underpinning addiction will facilitate its remediation. Some evidence suggests that the emotional properties of drug-paired stimuli themselves drive drug-procurement, while other evidence indicates that the expectation of reward elicited by the stimuli is sufficient to control drug-seeking. The current series of experiments aimed to explicate these seemingly contradictory data, by characterising the roles played in reward seeking by conditioned-stimulus-elicited emotion and expectation in non-dependent samples, before assessing their contribution in smokers. Further data suggest a role of personality in addictive behaviours, thus personality was assessed as a moderator of reward-seeking. Variations of a Pavlovian-to-instrumental transfer design, which tests the ability of reward-associated stimuli to modulate reward seeking, together with questionnaires of personality were applied. It was shown that outcome expectation was consistently necessary for cue-potentiated monetary-reward seeking, and similarly in smokers, cigarette outcome expectation was sufficient for cue-potentiated cigarette-reward seeking. Tentative evidence for the role of conditioned-stimulus emotional value in monetary-reward seeking was found, although this latter result requires scrutiny through additional research. Moderating influences of Extraversion and Neuroticism were found for cue-elicited emotion and outcome expectation, respectively. It is therefore proposed that reward expectancy is necessary for conditioned stimuli to control behaviour. The emotional properties of reward-predictive stimuli may be important for reward seeking in the absence of addiction, but when addiction to reward is present, control of reward seeking can occur via reward expectation only. Data from the role of personality, in moderating the effects of stimulus-elicited emotion or outcome expectation on reward-seeking behaviour, suggest that the control of behaviour by emotion may be facilitated by Extraversion, due to its propensity towards emotional processes, whereas control by expectation may be facilitated by Neuroticism, due to its inclination towards predictive learning

Fluidity of functional ensembles in the infralimbic cortex of rats during reward seeking

The medial prefrontal cortex (mPFC), specifically the prelimbic (PL) and the infralimbic region (IL), plays a crucial role during reward seeking behaviour. The IL specifically is involved in the control of reward seeking and has been implicated in the representation of different rewards. However, the precise representation of reward seeking behaviour on a neuronal network level within the IL remains elusive. To investigate neuronal ensembles during reward seeking in the IL of the mPFC in rats, an operant conditioning paradigm was combined with imaging of the intracellular calcium concentration ([Ca2+]i) as a proxy for neuronal activity. The latter is achieved using GRIN lenses and miniaturized head-mounted fluorescence microscopes. A frame trigger was used to synchronize the operant conditioning chambers with the [Ca2+]i data and an analysis pipeline was developed using a combination of custom designed Matlab classes and available open source software. Neurons were identified for three saccharin self-administration (SA) and one reinstatement (RE) session and then matched across sessions. Periods during which rats interacted with the operant conditioning setup were identified (e.g. lever presses and head entries into the reward port) and the corresponding [Ca2+]i transients were used to identify neurons coactive during distinct phases of reward seeking behaviour. Neurons were classified according to the time point of their activity relative to the sequence of actions consisting of the lever press and the time before, during, and after the head entry. This analysis revealed that subsets of neurons are preferentially active during distinct events of the reward seeking. Also, cells tuned to time points during the reward seeking did not appear or show tuning in all of the sessions. If they did show tuning, however, the phase of the reward seeking to which they showed tuning generally remained the same. Hence, the specific ensemble which is active during the reward seeking in each session changes. Individual neurons that are recruited into these ensembles, however, keep their tuning. Also, the composition of tuned neurons active during a specific behavioural phase remains stable. In addition, neurons that are active and tuned in multiple sessions do not appear to be arranged in a topology that can be identified with the methods used. In conclusion, the sequence of the reward seeking behaviour is encoded in neuronal ensembles of the IL cortex. These ensembles are formed from a larger pool of available neurons in each session. Neurons participating in these ensembles preferentially keep their tuning to a phase of the reward seeking, but may not be recruited to each of the ensembles. Thus, ensembles representing identical behavioural episodes in different sessions are not stable, but fluidly change their composition

A longitudinal high-risk study of adolescent anxiety, depression and parent-severity on the developmental course of risk-adjustment

Background Adolescence is associated with developments in the reward system and increased rates of emotional disorders. Familial risk for depression may be associated with disruptions in the reward system. However, it is unclear how symptoms of depression and anxiety influence the development of reward-processing over adolescence and whether variation in the severity of parental depression is associated with hyposensitivity to reward in a high-risk sample. Methods We focused on risk-adjustment (adjusting decisions about reward according to the probability of obtaining reward) as this was hypothesized to improve over adolescence. In a one-year longitudinal sample (N = 197) of adolescent offspring of depressed parents, we examined how symptoms of depression and anxiety (generalized anxiety and social anxiety) influenced the development of risk-adjustment. We also examined how parental depression severity influenced adolescent risk-adjustment. Results Risk-adjustment improved over the course of the study indicating improved adjustment of reward-seeking to shifting contingencies. Depressive symptoms were associated with decreases in risk-adjustment over time while social anxiety symptoms were associated with increases in risk-adjustment over time. Specifically, depression was associated with reductions in reward-seeking at favourable reward probabilities only, whereas social anxiety (but not generalized anxiety) led to reductions in reward-seeking at low reward probabilities only. Parent depression severity was associated with lowered risk-adjustment in offspring and also influenced the longitudinal relationship between risk-adjustment and offspring depression. Conclusions Anxiety and depression distinctly alter the pattern of longitudinal change in reward-processing. Severity of parent depression was associated with alterations in adolescent offspring reward-processing in a high-risk sample

Prefrontal cortex output circuits guide reward seeking through divergent cue encoding

The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations

Cerebellar BDNF promotes exploration and seeking for novelty

Approach system considered a motivational system that activates reward-seeking behavior is associated with exploration/impulsivity, whereas avoidance system considered an attentional system that promotes inhibition of appetitive responses is associated with active overt withdrawal. Approach and avoidance dispositions are modulated by distinct neurochemical profiles and synaptic patterns. However, the precise working of neurons and trafficking of molecules in the brain activity predisposing to approach and avoidance are yet unclear

Role of the Prefrontal Cortex in Reward Seeking Behaviors

Disorders associated with compulsive seeking of rewards, like binge-eating, are associated with abnormalities of the prefrontal cortex in humans, which is analogous to the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) in rodents. Although studies have examined the role of the mPFC in drug seeking behaviors, studies examining natural reward seeking behaviors (i.e. food and sucrose) are often unclear and contradictory. This dissertation aims to characterize the role of the PL and IL mPFC in operant sucrose seeking behaviors. We used pharmacological and chemogenetic tools to selectively inactivate the PL, IL and PL-nucleus accumbens (NAc) NAc during Fixed Ratio 1 (FR1), extinction, and cue-induced reinstatement. Furthermore, we describe the role of PL projections to the NAc in both highly-motivated rats (food restricted) and low-motivated rats (free fed) in operant sucrose seeking behaviors. Our results demonstrate that the IL subregion of the mPFC plays a role in the execution of reward seeking behaviors during extinction (i.e. well entries) and cue-induced reinstatement (i.e. nose poking). Additionally, our results demonstrate that the PL plays a role in inhibiting reward seeking during FR1 (i.e. nose pokes and rewarded well entries). However, the PL seems to play a role in promoting reward seeking during extinction (i.e. nose poking and well entries). We also observed that inactivating PL-NAc in food restricted rats during extinction and cue-induced reinstatement suppresses behaviors that do not result in reward delivery (i.e., inactive lever presses). In free fed rats, PL-NAc inhibits reward seeking behaviors (i.e. initiated trials) during cue-induced reinstatement. Our findings support our claim that the mPFC and its projections differentially control reward seeking behaviors depending on the behavioral (e.g., FR1, extinction, or cue-induced reinstatement) and motivational context (e.g., level of satiety) of animals. Understanding the function of the mPFC will give insight to understand and develop specialized therapies to treat and cure disorders like binge-eating, as well as other diseases associated with the mPFC, like substance use disorders

Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation

Motivated reward-seeking behaviours are governed by dopaminergic ventral tegmental area projections to the nucleus accumbens. In addition to dopamine, these mesoaccumbal terminals co-release other neurotransmitters including glutamate and GABA, whose roles in regulating motivated behaviours are currently being investigated. Here we demonstrate that loss of the E3-ubiquitin ligase, UBE3A, from tyrosine hydroxylase-expressing neurons impairs mesoaccumbal, non-canonical GABA co-release and enhances reward-seeking behaviour measured by optical self-stimulation