Viscerosensory signalling to the nucleus accumbens via the solitary tract nucleus.

The nucleus of the solitary tract (NTS) receives direct viscerosensory vagal afferent input that drives autonomic reflexes, neuroendocrine function and modulates behaviour. A subpopulation of NTS neurons project to the nucleus accumbens (NAc); however, the function of this NTS-NAc pathway remains unknown. A combination of neuroanatomical tracing, slice electrophysiology and fibre photometry was used in mice and/or rats to determine how NTS-NAc neurons fit within the viscerosensory network. NTS-NAc projection neurons are predominantly located in the medial and caudal portions of the NTS with 54 ± 7% (mice) and 65 ± 3% (rat) being TH-positive, representing the A2 NTS cell group. In horizontal brainstem slices, solitary tract (ST) stimulation evoked excitatory post-synaptic currents (EPSCs) in NTS-NAc projection neurons. The majority (75%) received low-jitter, zero-failure EPSCs characteristic of monosynaptic ST afferent input that identifies them as second order to primary sensory neurons. We then examined whether NTS-NAc neurons respond to cholecystokinin (CCK, 20 µg/kg ip) in vivo in both mice and rats. Surprisingly, there was no difference in the number of activated NTS-NAc cells between CCK and saline-treated mice. In rats, just 6% of NTS-NAc cells were recruited by CCK. As NTS TH neurons are the primary source for NAc noradrenaline, we measured noradrenaline release in the NAc and showed that NAc noradrenaline levels declined in response to cue-induced reward retrieval but not foot shock. Combined, these findings suggest that high-fidelity afferent information from viscerosensory afferents reaches the NAc. These signals are likely unrelated to CCK-sensitive vagal afferents but could interact with other sensory and higher order inputs to modulate learned appetitive behaviours.

State- and Circuit-Dependent Opponent Processing of Fear.

The presence of valence coding neurons in the basolateral amygdala (BLA) that form distinct projections to other brain regions implies functional opposition between aversion and reward during learning. However, evidence for opponent interactions in fear learning is sparse and may only be apparent under certain conditions. Here we test this possibility by studying the roles of the BLA→central amygdala (CeA) and BLA→nucleus accumbens (Acb) pathways in fear learning in male rats. First, we assessed the organization of these pathways in the rat brain. BLA→CeA and BLA→Acb pathways were largely segregated in the BLA but shared overlapping molecular profiles. Then we assessed activity of the BLA→CeA and BLA→Acb pathways during two different forms of fear learning-fear learning in a neutral context and fear learning in a reward context. BLA→CeA neurons were robustly recruited by footshock regardless of where fear learning occurred, whereas recruitment of BLA→Acb neurons was state-dependent because footshock only recruited this pathway in a reward context. Finally, we assessed the causal roles of activity in these pathways in fear learning. Photoinhibition of the BLA→CeA pathway during the footshock US impaired fear learning, regardless of where fear learning occurred. In contrast, photoinhibition of the BLA→Acb pathway augmented fear learning, but only in the reward context. Taken together, our findings show circuit- and state-dependent opponent processing of fear. Footshock activity in the BLA→Acb pathway limits how much fear is learned.

Chemogenetic activation of arcuate nucleus NPY and NPY/AgRP neurons increases feeding behaviour in mice.

Neuropeptide Y (NPY) plays a crucial role in controlling energy homeostasis and feeding behaviour. The role of NPY neurons located in the arcuate nucleus of the hypothalamus (Arc) in responding to homeostatic signals has been the focus of much investigation, but most studies have used AgRP promoter-driven models, which do not fully encompass Arc NPY neurons. To directly investigate NPY-expressing versus AgRP-expressing Arc neurons function, we utilised chemogenetic techniques in NPY-Cre and AgRP-Cre animals to activate Arc NPY or AgRP neurons in the presence of food and food-related stimuli. Our findings suggest that chemogenetic activation of the broader population of Arc NPY neurons, including AgRP-positive and AgRP-negative NPY neurons, has equivalent effects on feeding behaviour as activation of Arc AgRP neurons. Our results demonstrate that these Arc NPY neurons respond specifically to caloric signals and do not respond to non-caloric signals, in line with what has been observed in AgRP neurons. Activating Arc NPY neurons significantly increases food consumption and influences macronutrient selection to prefer fat intake.

A Cognitive Pathway to Persistent, Maladaptive Choice.

BACKGROUND: Correctly recognising that alcohol or other substances are causing problems is a necessary condition for those problems to spur beneficial behaviour change. Yet such recognition is neither immediate nor straightforward. Recognition that one's alcohol or drug use is causing negative consequences often occurs gradually. Contemporary addiction neuroscience has yet to make progress in understanding and addressing these recognition barriers, despite evidence that a lack of problem recognition is a primary impediment to seeking treatment. SUMMARY: Based on our recent empirical work, this article shows how recognition barriers can emerge from dual constraints on how we learn about the negative consequences of our actions. One constraint is imposed by the characteristics of negative consequences themselves. A second constraint is imposed by the characteristics of human cognition and information processing. In some people, the joint action of these constraints causes a lack of correct awareness of the consequences of their behaviour and reduced willingness to update that knowledge and behaviour when confronted with counterevidence. KEY MESSAGES: This "cognitive pathway" can drive persistent, maladaptive choice.

Translational research in punishment learning.

Punishment learning is learning of the causal relationship between responses and their adverse or undesirable consequences. Here, we review our translational approach for understanding whether, when, and how individuals differ in what they learn during punishment, and how these differences in learning may drive persistent poor or maladaptive decisions. We show that individual differences in punishment insensitivity can emerge from differences between individuals in what they learn about punishment (instrumental contingency knowledge), rather than differences in aversive valuation, reward valuation, general (impulsivity), or specific (habit) behavioral control. These differences in instrumental contingency knowledge are shared with and can be studied in other animals. Our approach has strong construct and predictive validity, providing a robust translational platform for studying how punishment learning and decision making may contribute to neuropsychiatric disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Reprioritizing motivations in addiction.

Drugs of abuse alter neuronal signaling.

Optogenetic recruitment of hypothalamic corticotrophin-releasing-hormone (CRH) neurons reduces motivational drive.

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stress- and reward-related brain regions drives these behaviors. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons 1 h/day for 5 consecutive days and showed increased acute stress-related behaviors and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioral changes may, in part, be driven by PVNCRH synaptic projections to the LH.

The Rescorla-Wagner model, prediction error, and fear learning.

The Rescorla-Wagner model remains one of the most important and influential theoretical accounts of the conditions under which Pavlovian learning occurs. Moreover, the experimental approaches that inspired the model continue to provide powerful behavioral tools to advance mechanistic understanding of how we and other animals learn to fear and learn to reduce fear. Here we consider key features of the Rescorla-Wagner model as applied to study of fear learning. We review evidence for key insights of the model. First, learning to fear and learning to reduce fear are governed by a common, signed prediction error. Second, this error drives variations in effectiveness of the shock US that are causal to whether and how much fear is learned or lost during a conditioning trial. We also consider behavioral and neural findings inconsistent with the model and which will be essential to understand and advance understanding of fear learning.

A cognitive pathway to punishment insensitivity.

Individuals differ in their sensitivity to the adverse consequences of their actions, leading some to persist in maladaptive behaviors. Two pathways have been identified for this insensitivity: a motivational pathway based on excessive reward valuation and a behavioral pathway based on autonomous stimulus-response mechanisms. Here, we identify a third, cognitive pathway based on differences in punishment knowledge and use of that knowledge to suppress behavior. We show that distinct phenotypes of punishment sensitivity emerge from differences in what people learn about their actions. Exposed to identical punishment contingencies, some people (sensitive phenotype) form correct causal beliefs that they use to guide their behavior, successfully obtaining rewards and avoiding punishment, whereas others form incorrect but internally coherent causal beliefs that lead them to earn punishment they do not like. Incorrect causal beliefs were not inherently problematic because we show that many individuals benefit from information about why they are being punished, revaluing their actions and changing their behavior to avoid further punishment (unaware phenotype). However, one condition where incorrect causal beliefs were problematic was when punishment is infrequent. Under this condition, more individuals show punishment insensitivity and detrimental patterns of behavior that resist experience and information-driven updating, even when punishment is severe (compulsive phenotype). For these individuals, rare punishment acted as a "trap," inoculating maladaptive behavioral preferences against cognitive and behavioral updating.

Pathways to the persistence of drug use despite its adverse consequences.

The persistence of drug taking despite its adverse consequences plays a central role in the presentation, diagnosis, and impacts of addiction. Eventual recognition and appraisal of these adverse consequences is central to decisions to reduce or cease use. However, the most appropriate ways of conceptualizing persistence in the face of adverse consequences remain unclear. Here we review evidence that there are at least three pathways to persistent use despite the negative consequences of that use. A cognitive pathway for recognition of adverse consequences, a motivational pathway for valuation of these consequences, and a behavioral pathway for responding to these adverse consequences. These pathways are dynamic, not linear, with multiple possible trajectories between them, and each is sufficient to produce persistence. We describe these pathways, their characteristics, brain cellular and circuit substrates, and we highlight their relevance to different pathways to self- and treatment-guided behavior change.

Nucleus of the solitary tract A2 neurons control feeding behaviors via projections to the paraventricular hypothalamus.

Hindbrain NTS neurons are highly attuned to internal physiological and external environmental factors that contribute to the control of food intake but the relevant neural phenotypes and pathways remain elusive. Here, we investigated the role of NTS A2 neurons and their projections in the control of feeding behaviors. In male TH Cre rats, we first confirmed selective targeting of NTS A2 neurons and showed that chemogenetic stimulation of these neurons significantly suppressed dark cycle food intake, deprivation re-feed and high fat diet intake. Despite reducing intake, activation of NTS A2 neurons had no effect on food approach, anxiety-like behaviors, locomotor activity, blood glucose levels nor did it induce nausea/malaise, thus revealing a selective role for these neurons in the consummatory aspect of food intake control. Pathway-specific mapping and manipulation of NTS A2 neurons showed that these effects were mediated by NTS A2 neurons projecting to the paraventricular nucleus of the hypothalamus (PVH) because chemogenetic activation of these projections, but not projections to bed nucleus of the stria terminalis (BNST), reduced food intake. Cell-type specific analyses demonstrated that activation of NTS A2 neurons recruited both PVH oxytocin (OT)- and corticotropin-releasing factor (CRF)-expressing neurons, and plasma analyses showed increased plasma corticosterone following NTS A2 stimulation. While we also showed that chemogenetic inhibition of NTS A2 neurons attenuated the intake inhibitory effects of CCK, the specificity of transgene expression was low. Together, these findings showed that NTS A2 neurons are sufficient to control the consummatory aspects of feeding, regardless of energy status or food palatability and identified their projections to PVH, but not BNST, in food intake control.

The role of impulsivity in the relationship between affect and alcohol consumption in young adults.

BACKGROUND: Theoretical models of alcohol use posit that individuals consume alcohol to ameliorate negative affect or to heighten positive affect. It is important, however, to consider the influence of factors that may determine an individual's tendency to consume excessive amounts of alcohol under positive and negative circumstances. Thus, the current study examined a large sample of young adults to clarify whether positive and negative affect predict total alcohol consumption on drinking days and whether facets of impulsivity moderate these relationships. METHODS: Six-hundred ninety-three young adults (Mage = 19.71 years, SD = 2.04; female = 62.9%) completed the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scales at baseline followed by daily measures of positive and negative affect and self-reported alcohol use for 13 days. Generalized linear mixed models were specified to assess the role of pre-consumption affect on total drinks consumed across drinking days and to determine the moderating effect of each BIS/BAS subscale. RESULTS: Participants were significantly more likely to drink in greater quantities on occasions preceded by higher positive affect but not negative affect. While fun-seeking positively predicted total drinks consumed, there were no significant interaction effects between the BIS/BAS subscales and affect on total drinks consumed. CONCLUSIONS: These findings challenge existing affect regulation models and have implications for ecological momentary interventions aimed at addressing hazardous drinking behaviors.

Can we enhance the clinical efficacy of cognitive and psychological approaches to treat substance use disorders through understanding their neurobiological mechanisms?

Despite decades of research in the field of addiction, relapse rates for substance use disorders remain high. Consequently, there has been growing focus on providing evidence-based treatments for substance use disorders, resulting in the increased development and use of cognitive and psychological interventions. Such treatment approaches, including contingency management, community-reinforcement approach, and cognitive bias modification, have shown promising clinical efficacy in reducing substance use and promoting abstinence during treatment. However, these interventions are still somewhat limited in achieving sustained periods of abstinence post-treatment. The neurobiological mechanisms underpinning these treatment approaches remain largely unknown and under-studied, in part, due to a lack of translational animal models. The adoption of a reverse translational approach may assist in development of more representative models that can facilitate elucidation of the mechanisms behind these clinically relevant interventions. This review examines our current understanding of addiction neurobiology from clinical, preclinical research and existing animal models, and considers how the efficacy of such behavioral-oriented interventions alone, or in combination with pharmacotherapy, may be enhanced to improve treatment outcomes.

A Corticothalamic Circuit Trades off Speed for Safety during Decision-Making under Motivational Conflict.

Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death, whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach-avoidance decisions under motivational conflict in male mice. Then we used cognitive modeling to show that these dynamics reflect the speeded decision-making mechanisms used by humans and nonhuman primates, with mice trading off decision speed for safety of choice when danger loomed. Using calcium imaging in paraventricular thalamus and optogenetic inhibition of the prelimbic cortex to paraventricular thalamus pathway, we show that this speed-safety trade off occurs because increases in paraventricular thalamus activity increase decision caution, thereby increasing approach-avoid decision times in the presence of danger. Our findings demonstrate that a discrete brain circuit involving the paraventricular thalamus and its prefrontal input adjusts decision caution during motivational conflict, trading off decision speed for decision safety when danger is close. We identify the corticothalamic pathway as central to cognitive control during decision-making under conflict.SIGNIFICANCE STATEMENT Foraging animals balance the need to seek food and energy against the conflicting needs to avoid injury and predation. This competition is fundamental to survival but rarely has a stable, correct solution. Here we show that approach-avoid decisions under motivational conflict involve strategic adjustments in decision caution controlled via a top-down corticothalamic pathway from the prelimbic cortex to the paraventricular thalamus. We identify a novel corticothalamic mechanism for cognitive control that is applicable across a range of motivated behaviors and mark paraventricular thalamus and its prefrontal cortical input as targets to remediate the deficits in decision caution characteristic of unsafe and impulsive choices.

The activity of ventral tegmental area dopamine neurons during shock omission predicts safety learning.

We studied the role of dopamine [tyrosine hydroxylase (TH)] neurons in the rat ventral tegmental area (VTA) in safety learning. First, we used an AX +/BX-discrimination procedure to establish conditioned stimulus (CS) B as a learned safety signal that passed both summation and retardation tests of conditioned inhibition. Then, we combined this procedure with fiber photometry in TH-Cre rats to study the activity of VTA dopamine neurons during safety learning. We show that whereas footshock is associated with calcium transients in TH neurons across the VTA, shock omission during safety learning is selectively associated with calcium transients in dopamine neurons in the medial but not lateral VTA. Moreover, the magnitude of medial VTA calcium transients during shock omission accurately predicts the amount of safety that is learned and expressed during summation testing. Our findings are consistent with a common medial VTA dopamine mechanism contributing to the learned inhibition of fear in extinction and safety. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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 earning a reward. 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.

The Roles of Basolateral Amygdala Parvalbumin Neurons in Fear Learning.

The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV)-expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, activity profiles of these interneurons across the course of fear learning, and whether or how these change across the course of learning all remain poorly understood. Here, we used PV cell-type-specific recording and manipulation approaches in male transgenic PV-Cre rats during pavlovian fear conditioning to address these issues. We show that activity of BLA PV neurons during the moments of aversive reinforcement controls fear learning about aversive events, but activity during moments of nonreinforcement does not control fear extinction learning. Furthermore, we show expectation-modulation of BLA PV neurons during fear learning, with greater activity to an unexpected than expected aversive unconditioned stimulus (US). This expectation-modulation was specifically because of BLA PV neuron sensitivity to aversive prediction error. Finally, we show that BLA PV neuron function in fear learning is conserved across these variations in prediction error. We suggest that aversive prediction-error modulation of PV neurons could enable BLA fear-learning circuits to retain selectivity for specific sensory features of aversive USs despite variations in the strength of US inputs, thereby permitting the rapid updating of fear associations when these sensory features change.SIGNIFICANCE STATEMENT The capacity to learn about sources of danger in the environment is essential for survival. This learning depends on complex microcircuitries of inhibitory interneurons in the basolateral amygdala. Here, we show that parvalbumin-positive GABAergic interneurons in the rat basolateral amygdala are important for fear learning during moments of danger, but not for extinction learning during moments of safety, and that the activity of these neurons is modulated by expectation of danger. This may enable fear-learning circuits to retain selectivity for specific aversive events across variations in expectation, permitting the rapid updating of learning when aversive events change.