Biology subjects

Moghaddam, B.

Publications and source records attributed to Moghaddam, B..

14 recordsLinked to original sources

bioRxiv2026

Psilocybin asymmetrically modulates outcome-based choice and cortical processing under uncertainty

Emerging clinical research with psilocybin highlights the value of the psychedelic experience on successful treatment of a multitude of psychiatric disorders. While the psychedelic trip or clinical support procedures cannot be modeled in rodents, neural processes critical to meta-learning and flexible modification of previously learned strategies can be quantified during psilocybin exposure. Here we applied computational modeling and single unit recordings from medial prefrontal cortex to characterize the effect of psilocybin using a value-based probabilistic choice task. Psilocybin improved choice selection in uncertain contexts and shifted reinforcement learning rate bidirectionally, enhancing updating from rewarded, while reducing updating from unrewarded, actions. These behavioral changes coincided with selective shifts in the neural encoding of task features including enhanced neural representation of rewarded, and diminished representation of unrewarded, outcomes. Collectively these data indicate that psilocybin improves choice selection in uncertain contexts by reweighing cortical coding in a way that favors learning from positive new information over prospective actions.

neuroscience↗

bioRxiv2024

Adolescent alcohol consumption produces long term alterations in response inhibition and orbitofrontal-striatal activity in a sex-specific manner

Alcohol use disorder (AUD) is strongly associated with initiation of drinking during adolescence. Little is known about neural mechanisms that produce the long-term detrimental effects of adolescent drinking. A critical feature of AUD is deficits in response inhibition, or the ability to withhold a reward-seeking response. Here we sought to determine if adolescent drinking affects response inhibition and encoding of neural events by the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS), two regions critical for expression of response inhibition. Adolescent male and female rats were given access to alcohol for four hours a day for five consecutive days. Then, rats were tested in a cued response inhibition task as adolescents or adults while we recorded concomitantly from the OFC and DMS. Adolescent voluntary alcohol drinking impaired response inhibition and increased alcohol drinking in adult male but not female rats. Adolescent alcohol drinking also resulted in sex-specific effects on both unit firing and local field potential measures in the OFC and DMS during premature and correct actions. Collectively, these data suggest sex-specific effects of adolescent alcohol drinking on response inhibition and corresponding alterations in cortical-striatal circuitry. HighlightsO_LIModerate adolescent alcohol drinking disrupts adult response inhibition C_LIO_LIAction encoding in the OFC and DMS changes after adolescent alcohol drinking C_LIO_LIOFC-DMS connectivity is altered in males after adolescent alcohol drinking C_LIO_LIAdolescent alcohol drinking promotes increased alcohol intake in adult males C_LI

neuroscience↗

bioRxiv2024

Reductions of Grin2a in adolescent dopamine neurons confers aberrant salience and related psychosis phenotype

Psychosis is a hallmark of schizophrenia. It involves a collection of symptoms that are typically associated with disrupted dopamine signaling and emerges during adolescence or early adulthood. Most schizophrenia-associated genes, however, involve glutamatergic or other ubiquitous targets that do not explain the latent expression of psychosis or dopaminergic abnormalities. Here, we describe an etiologically relevant model for the adolescent onset of dopamine-related dysfunction in schizophrenia. We focused on GRIN2A, the gene encoding the GluN2A subunit of the NMDA receptor, as both the common loss-of-function variants and the rare missense variants in this gene are risk factors for schizophrenia. We find that GluN2A levels distinctly decline in dopamine neuron-containing regions throughout adolescence while remaining stable in other regions. This suggested that adolescent dopamine neurons may be particularly vulnerable to further reductions in GluN2A caused by a damaging variant of GRIN2A. Consistent with this idea, we find that selective knockout of Grin2a in adolescent rat dopamine neurons results in a psychosis-relevant behavioral phenotype. This manipulation also reduced dopamine release in response to unexpected outcomes in young adults, reflective of prediction error signaling abnormalities observed in the clinical population. These data provide mechanistic insight into how GRIN2A mutations may contribute to the delayed onset of dopamine-related symptoms and provide a model for identifying course altering treatments for schizophrenia.

neuroscience↗

bioRxiv2024

Reward and punishment contingency shifting reveals distinct roles for VTA dopamine and GABA neurons in behavioral flexibility

In dynamic environments where stimuli predicting rewarding or aversive outcomes unexpectedly change, it is critical to flexibly update behavior while preserving recollection of previous associations. Dopamine and GABA neurons in the ventral tegmental area (VTA) are implicated in reward and punishment learning, yet little is known about how each population adapts when the predicted outcome valence changes. We measured VTA dopamine and GABA population activity while male and female rats learned to associate three discrete auditory cues to three distinct outcomes: reward, punishment, or no outcome within the same session. After learning, the reward and punishment cue-outcome contingencies were reversed, and subsequently rereversed. As expected, the dopamine population rapidly adapted to learning and contingency reversals by increasing the response to appetitive stimuli and decreasing the response to aversive stimuli. In contrast, the GABA population increased activity to all sensory events regardless of valence, including the neutral cue. Reversing learned contingencies selectively influenced GABA responses to the reward-predictive cue, prolonging increased activity within and across sessions. The observed valence-specific dissociations in the directionality and temporal progression of VTA dopamine and GABA calcium activity indicates that these populations are independently recruited and serve distinct roles during appetitive and aversive associative learning and contingency reversal.

neuroscience↗

bioRxiv2023

Complementary roles of orbitofrontal and prelimbic cortices in adaption of reward motivated actions to learned anxiety.

BackgroundAnxiety is a common symptom of several mental health disorders and adversely affects motivated behaviors. Anxiety can emerge from associating risk of future harm while engaged in goal-guided actions. Using a recently developed behavioral paradigm to model this aspect of anxiety, we investigated the role of two cortical subregions, the prelimbic medial frontal cortex (PL) and lateral orbitofrontal cortex (lOFC), which have been implicated in anxiety and outcome expectation, in flexible representation of actions associated with harm risk. MethodsA seek-take reward-guided instrumental task design was used to train animals to associate the seek action with a variable risk of punishment. After learning, animals underwent extinction training for this association. Fiber photometry was used to measure and compare neuronal activity in PL and lOFC during learning and extinction. ResultsAnimals increased action suppression in response to punishment contingencies. This increase dissipated after extinction training. These behavioral changes were associated with region specific changes in neuronal activity. PL neuronal activity preferentially adapted to threat of punishment whereas lOFC activity adapted to safe aspects of the task. Moreover, correlated activity between these regions was suppressed during actions associated with harm risk suggesting that these regions may guide behavior independently under anxiety. ConclusionsThese findings suggest the PL and lOFC serve distinct but complementary roles in the representation of learned anxiety. This dissociation may provide a mechanism for how overlapping cortical systems are implicated in reward-guided action execution during anxiety.

neuroscience↗

bioRxiv2023

Acute psilocybin enhances cognitive flexibility in rats

Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2A receptor antagonist ketanserin blocked psilocybins effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybins pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.

neuroscience↗

bioRxiv2022

Learning of probabilistic punishment as a model of anxiety produces changes in action but not punishment encoding in the dmPFC and VTA

Previously, we developed a novel model for anxiety during motivated behavior by training rats to perform a task where actions executed to obtain a reward were probabilistically punished and observed that after learning, neuronal activity in the ventral tegmental area (VTA) and dorsomedial prefrontal cortex (dmPFC) encode the relationship between action and punishment risk (Park & Moghaddam, 2017). Here we used male and female rats to expand on the previous work by focusing on neural changes in the dmPFC and VTA that were associated with the learning of probabilistic punishment, and with anxiolytic treatment with diazepam after learning. We find that adaptive neural responses of dmPFC and VTA during the learning of anxiogenic contingencies are independent from the punishment experience and occur primarily during the peri-action period. Our results further identify peri-action ramping of VTA neural activity, and VTA-dmPFC correlated activity, as potential markers for the anxiolytic properties of diazepam.

neuroscience↗

bioRxiv2021

Adolescent dopamine neurons represent reward differently during action and state guided learning

The neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN). We find that in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning suggesting that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar further supporting the notion that differences in reward response in each paradigm are due to differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons such as dopamine cell number and size were similar in the VTA and SN but there were age differences in baseline firing rate, stimulated release and correlated spike activity suggesting that differences in reward responsiveness by adolescent dopamine neurons are not due to differences in intrinsic properties of these neurons but engagement of different networks.

neuroscience↗

bioRxiv2019

Sex differences in reward- and punishment-guided actions

Differences in the prevalence and presentation of psychiatric illnesses in men and women suggest that neurobiological sex differences confer vulnerability or resilience in these disorders. Rodent behavioral models are critical for understanding the mechanisms of these differences. Reward processing and punishment avoidance are fundamental dimensions of the symptoms of psychiatric disorders. Here we explored sex differences along these dimensions using multiple and distinct behavioral paradigms. We found no sex difference in reward-guided associative learning but a faster punishment-avoidance learning in females. After learning, females were more sensitive than males to probabilistic punishment but less sensitive when punishment could be avoided with certainty. No sex differences were found in reward-guided cognitive flexibility. Thus, sex differences in goal-directed behaviors emerged selectively when there was an aversive context. These differences were critically sensitive to whether the punishment was certain or unpredictable. Our findings with these new paradigms provide conceptual and practical tools for investigating brain mechanisms that account for sex differences in susceptibility to anxiety and impulsivity. They may also provide insight for understanding the evolution of sex-specific optimal behavioral strategies in dynamic environments.

animal behavior and cognition↗

bioRxiv2018

Dopamine modulation of prefrontal cortex activity is manifold and operates at multiple temporal and spatial scales

While the function of dopamine in subcortical structures is largely limited to reward and movement, dopamine neurotransmission in the prefrontal cortex (PFC) is critical to a multitude of temporally and functionally diverse processes such as attention, working memory, behavioral flexibility, action selection, and stress adaptation. How does dopamine influence PFC computation of multiple temporally diverse functions? Here we find causation between sustained and burst patterns of phasic dopamine neuron activation and contemporaneous modulation of PFC neuronal activity at multiple spatio-temporal scales. These include a multidirectional and weak impact on individual PFC neuron rate activity and a robust influence on coordinated ensemble activity, gamma oscillations, and gamma-theta coupling that persisted for minutes. In addition, PFC network responses to burst pattern of dopamine firing were selectively strengthened in behaviorally active states. Thus, dopamine modulation of PFC is spatiotemporally diverse and is dictated by the pattern of dopamine neuron activation and behavioral state. These findings provide insight on the multiplex pattern of modulation by dopamine that may influence PFC computation of temporally diverse functions.

neuroscience↗

bioRxiv2018

Efficient sorting of single-unit activity from midbrain cells using KiloSort is as accurate as manual sorting.

Extracting single-unit activity from in vivo extracellular neural electrophysiology data requires sorting spikes from background noise and action potentials from multiple cells in order to identify the activity of individual neurons. Typically this has been achieved by algorithms that employ principal component analyses followed by manual allocation of spikes to individual clusters based on visual inspection of the waveform shape. This method of manual sorting can give varying results between human operators and is highly time-consuming, especially in recordings with higher levels of background noise. To address these problems, automatic sorting algorithms have begun to gain popularity as viable methods for sorting electrophysiological data, although little is known about the use of these algorithms with neural data from midbrain recordings. KiloSort is a relatively new algorithm that automatically clusters raw data which can then be manually curated. In this report, we compare results of manually-sorted and KiloSort-processed recordings from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Sorting with KiloSort required substantially less time to complete, while yielding comparable and consistent results. We conclude that the use of KiloSort to identify single units from multi-channel recording in the VTA and SNc is accurate and efficient.

neuroscience↗

bioRxiv2017

Discrete and coordinated encoding of punishment contingent on rewarded actions by prefrontal cortex and VTA

Actions motivated by a rewarding outcome are often associated with a risk of punishment. Little is known about the neural representation of punishment that is contingent on reward-guided behavior. We modeled this circumstance by using a task where actions were consistently rewarded but probabilistically punished. Spike activity and local field potentials were recorded during this task simultaneously from VTA and mPFC, two reciprocally connected regions implicated in both reward-seeking and aversive behavioral states. At the single unit level, we found that ensembles of VTA and mPFC neurons encode the contingency between action and punishment. At the network level, we found that coherent theta oscillations synchronize the VTA and mPFC in a bottom-up direction, effectively phase-modulating the neuronal spike activity in the two regions during punishment-free actions. This synchrony declined as a function of punishment contingency, suggesting that during reward-seeking actions, risk of punishment diminishes VTA-driven neural synchrony between the two regions.

neuroscience↗

bioRxiv2017

Burst Activation Of Dopamine Neurons Produces Prolonged Post-Burst Availability Of Actively Released Dopamine

Both phasic and tonic modes of neurotransmission are implicated in critical functions assigned to dopamine. In learning, for example, sub-second phasic responses of ventral tegmental area (VTA) dopamine neurons to salient events serve as teaching signals, but learning is also interrupted by dopamine antagonists administered minutes after training. Our findings bridge the multiple timescales of dopamine neurotransmission by demonstrating that burst stimulation of VTA dopamine neurons produces a prolonged post-burst increase (> 20 min) of extracellular dopamine in nucleus accumbens and prefrontal cortex. This elevation is not due to spillover from the stimulation surge but depends on impulse flow-mediated dopamine release. We identified Rho-mediated internalization of dopamine transporter as a mechanism responsible for prolonged availability of actively released dopamine. These results demonstrate that phasic and tonic dopamine neurotransmission can be a continuum and may explain why both modes of signaling are critical for motivational and cognitive functions associated with dopamine.

neuroscience↗

bioRxiv2016

Ventral tegmental area neurons use an ensemble code for representing information about ongoing actions

Multiple and unpredictable numbers of actions are often required to achieve a goal. In order to organize behavior and allocate effort so that optimal behavioral policies can be selected, it is necessary to continually monitor ongoing actions. Real-time processing of information related to actions and outcomes is typically assigned to the prefrontal cortex and basal ganglia, but also depends on midbrain regions, especially the ventral tegmental area (VTA). We were interested in how individual VTA neurons, as well as networks within the VTA, encode salient events when an unpredictable number of serial actions are required to obtain a reward. We recorded from ensembles of putative dopamine and non-dopamine neurons in the VTA as animals performed multiple cued trials in a recording session where, in each trial, serial actions were randomly rewarded. While averaging population activity did not reveal a response pattern, we observed that different neurons selectively tuned to low, medium, or high numbered actions in a trial. This preferential tuning of putative dopamine and non-dopamine VTA neurons to different subsets of actions in a trial allowed information about binned action number to be decoded from the ensemble activity. At the network level, tuning curve similarity was positively associated with action-evoked noise correlations, suggesting that action number selectivity reflects functional connectivity within these networks. Analysis of phasic responses to cue and reward revealed that the requirement to execute multiple and uncertain numbers of actions weakens both cue-evoked responses and cue-reward response correlation. The functional connectivity and ensemble coding scheme that we observe here may allow VTA neurons to cooperatively provide a real-time account of ongoing behavior. These computations may be critical to cognitive and motivational functions that have long been associated with VTA dopamine neurons.

neuroscience↗