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Jean-Richard-dit-Bressel, P.

Publications and source records attributed to Jean-Richard-dit-Bressel, P..

10 recordsLinked to original sources

Representational geometry of punishment learning across basolateral amygdala neurons

Punishment learning allows animals to suppress actions that cause harm while maintaining actions that earn reward. Although the basolateral amygdala is necessary for punishment learning, how its population activity changes across learning, and how this activity reflects an action's consequences, remain unknown. We used longitudinal calcium imaging to track 1,147 basolateral amygdala neurons in male mice across instrumental training, punishment, choice test, and punishment extinction. Punishment learning transformed basolateral amygdala neuron activity associated with the punished action. This activity diverged from that associated with the unpunished action and became aligned with activity evoked by the punisher itself. This alignment was action and contingency specific. It preserved the direction of individual neurons' responses to the punisher: neurons activated by the punisher become more activated by the punished action alone, whereas neurons inhibited by the punisher become more inhibited by the punished action alone. We then asked whether reward and punishment were encoded separately or on a common value dimension across basolateral amygdala neurons. Punishment added a strong shock component to action-related activity without reducing its reward component, while reward and shock themselves occupied largely orthogonal population directions. Thus, during punishment learning, basolateral amygdala population activity can encode opposing consequences of the same action instead of simply changing what that action is worth.

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The brain architecture of punishment learning

Learning which actions cause harm is essential for survival, yet how the brain transforms this knowledge into adaptive control of behavior remains unclear. We combined whole-brain analysis, multisite chemogenetic silencing, spatial transcriptomics, and longitudinal calcium imaging to map how punishment learning reorganizes brain networks across scales. Learning reshaped mesoscale community organization into a network anchored by the amygdala, subthalamic-hypothalamic zone, and ventral midbrain tegmentum. These regions contributed distinct components of adaptive avoidance and engaged diverse transcriptional programs across multiple neuronal subclasses. Within this network, the amygdala acted as a hub, partitioning action and outcome information and remapping neural geometry to segregate punished from safe actions. Together, these results identify a multiscale neural architecture through which aversive experience can be transformed into flexible behavioral control.

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Relationships between phenotypic differences in punishment behaviour and prefrontal cortex network engagement

Avoiding actions with negative consequences is fundamental to adaptive behaviour, yet individuals differ drastically in their tendencies to avoid to punishment. Using a conditioned punishment task in male and female rats, we replicate findings of a bimodal distribution of punishment avoidance, and identify four distinct behavioural phenotypes (Sensitive, Hypersensitive, Insensitive, Generalised) that differed in their punishment avoidance, unpunished reward-seeking, and Pavlovian fear. We examined how these phenotypic differences related to c-Fos (transcriptional activity marker) across prefrontal cortex (PFC) regions. While region-level c-Fos differences were minimal, covariance and graph-theoretic analyses revealed three functional PFC networks predominantly composed of medial PFC, ventrolateral PFC, or sensorimotor regions. Activity in the ventrolateral PFC network predicted punishment avoidance, while activity in the medial PFC network predicted generalised suppression during initial punishment learning. These findings suggest phenotypic differences in punishment sensitivity is underpinned by differential recruitment of distinct cortical networks that drive adaptive versus maladaptive responses to negative outcomes.

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FiPhoPHA - A fiber photometry python package for post-hoc analysis

Fiber photometry is a neuroscience technique that can continuously monitor in vivo fluorescence to assess population neural activity or neuropeptide/transmitter release in freely behaving animals. Despite the widespread adoption of this technique, methods to statistically analyse data in an unbiased, objective, and easily adopted manner are lacking. Various pipelines for data analysis exist, but they are often system-specific, only for pre-processing data, and/or lack usability. Current post hoc statistical approaches involve inadvertently biased user-defined time-binned averages or area under the curve analysis. To date, no post-hoc user-friendly tool with few assumptions for a standardised unbiased analysis exists, yet such a tool would improve reproducibility and statistical reliability for all users. Hence, we have developed a user-friendly post hoc statistical analysis package in Python that is easily downloaded and applied to data from any fiber photometry system. This Fiber Photometry Post Hoc Analysis (FiPhoPHA) package incorporates a variety of tools, a downsampler, bootstrapped confidence intervals (CIs) for analyzing peri-event signals between groups and compared to baseline, and permutation tests for comparing peri-event signals across comparison periods. We also include the ability to quickly and efficiently sort the data into mean time bins, if desired. This provides an open-source, user-friendly python package for unbiased and standardised post-hoc statistical analysis to improve reproducibility using data from any fiber photometry system.

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Instrumental Punishment Learning Enhances the Intrinsic Excitability of Basolateral Amygdala Neurons

The basolateral amygdala (BLA) is a structure that is critical for forming Pavlovian and instrumental emotional associations. Previous studies have established that Pavlovian fear conditioning increases the intrinsic excitability of BLA projection neurons. Learning-associated increases in excitability are hypothesised to facilitate the induction of synaptic plasticity and integration of neurons into functional learning circuits. Here, we examined whether instrumental learning produces similar changes in intrinsic excitability. Male and Female Long Evans rats were trained to lever press for a food reward and subsequently split into 3 behavioural groups; punished, yoked, and reward. Punished rats received response-contingent footshocks, yoked rats received response-independent footshocks, and reward rats received no shock. Intrinsic excitability was measured as the number of action potentials (APs) evoked by a series of depolarising current injections during whole-cell patch clamp recordings. Reward learning increased the intrinsic excitability of BLA projection neurons compared to naive controls. Punishment training maintained excitability and excitability was correlated with performance on the punishment task. Response-independent footshocks arrested reward-associated increases in excitability, reverting the BLA neurons to a naive state. Group differences were observed in AP half-width and the current underlying the post-burst AHP. Together, these findings show that instrumental reward learning enhances the intrinsic excitability of BLA projection neurons, potentially supporting action-outcome encoding by promoting synaptic plasticity and circuit integration. The results also suggest that different forms of learning engage distinct biophysical adaptations. A mechanistic understanding of the neurobiology underlying instrumental association learning may help inform the development of treatments for psychiatric disorders characterized by deficits in this process, such as major depressive disorder and conduct disorder.

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Role of anterior insula cortex in context-induced relapse of nicotine-seeking

Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the key barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labelling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction imposed abstinence.

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Instrumental aversion coding in the basolateral amygdala and its reversion by a benzodiazepine

Punishment involves learning the relationship between actions and their adverse consequences. Both the acquisition and expression of punishment learning depend on the basolateral amygdala (BLA), but how BLA supports punishment remains poorly understood. To address this, we measured calcium (Ca2+) transients in BLA principal neurons during punishment. Male rats were trained to press two individually presented levers for food; when one of these levers also yielded aversive footshock, responding on this punished lever decreased relative to the other, unpunished lever. In rats with the Ca2+indicator GCaMP6f targeted to BLA principal neurons, we observed excitatory activity transients to the footshock punisher and inhibitory transients to lever-presses. Critically, as rats learned punishment, activity around the punished response transformed from inhibitory to excitatory and similarity analyses showed that these punished lever-press transients resembled BLA transients to the punisher itself. Systemically administered benzodiazepine (midazolam) selectively alleviated punishment. Moreover, the degree to which midazolam alleviated punishment was associated with how much punished response-related BLA transients reverted to their pre-punishment state. Together, these findings show that punishment learning is supported by aversion-coding of instrumental responses in the BLA and that the anti-punishment effects of benzodiazepines are associated with a reversion of this aversion coding.

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Punishment insensitivity in humans is due to failures in instrumental contingency learning

Punishment maximises the probability of our individual survival by reducing behaviours that cause us harm, and also sustains trust and fairness in groups essential for social cohesion. However, some individuals are more sensitive to punishment than others and these differences in punishment sensitivity have been linked to a variety of decision-making deficits and psychopathologies. The mechanisms for why individuals differ in punishment sensitivity are poorly understood, although recent studies of conditioned punishment in rodents highlight a key role for punishment contingency detection (Jean-Richard-dit-Bressel et al., 2019). Here we applied a novel "Planets & Pirates" conditioned punishment task in humans, allowing us to identify the mechanisms for why individuals differ in their sensitivity to punishment. We show that punishment sensitivity is bimodally distributed in a large sample of normal participants. Sensitive and insensitive individuals equally liked reward and showed similar rates of reward-seeking. They also equally disliked punishment and did not differ in their valuation of cues that signalled punishment. However, sensitive and insensitive individuals differed profoundly in their capacity to detect and learn volitional control over aversive outcomes. Punishment insensitive individuals did not learn the instrumental contingencies, so they could not withhold behaviour that caused punishment and could not generate appropriately selective behaviours to prevent impending punishment. These differences in punishment sensitivity could not be explained by individual differences in behavioural inhibition, impulsivity, or anxiety. This bimodal punishment sensitivity and these deficits in instrumental contingency learning are identical to those dictating punishment sensitivity in non-human animals, suggesting that they are general properties of aversive learning and decision making.

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Medial Orbitofrontal Cortex Regulates Instrumental Conditioned Punishment, but not Pavlovian Conditioned Fear

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsion and compulsive disorders. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented instrumental conditioned punishment learning in a manner that could not be attributed to differences in Pavlovian conditioned fear. We then showed that increasing the frequency of punishing outcomes allowed mOFC-lesioned animals to overcome their initial deficit. Our second experiment demonstrated that the retrieval of instrumental punishment is also mOFC-dependent, as mOFC lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent the re-acquisition of conditioned punishment that was learned prior to lesions being administered. Together, these results reveal that the mOFC does indeed regulate punishment learning and retrieval in a manner that is disassociated from any role in Pavlovian fear learning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.

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Punishment insensitivity emerges from impaired contingency detection, not aversion insensitivity or reward dominance

Our behaviour is shaped by its consequences - we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, i.e. in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats (n = 48; 18 female) trained in a task permitting concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.

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