RESUMO
PI3-kinase (PI3K) is an intracellular signaling complex that is stimulated upon cocaine exposure and linked with the behavioral consequences of cocaine. We recently genetically silenced the PI3K p110ß subunit in the medial prefrontal cortex following repeated cocaine in mice, reinstating the capacity of these mice to engage in prospective goal-seeking behavior. In the present short report, we address two follow-up hypotheses: 1) The control of decision-making behavior by PI3K p110ß is attributable to neuronal signaling, and 2) PI3K p110ß in the healthy (i.e., drug-naïve) medial prefrontal cortex has functional consequences in the control of reward-related decision-making strategies. In Experiment 1, we found that silencing neuronal p110ß improved action flexibility following cocaine. In Experiment 2, we reduced PI3K p110ß in drug-naïve mice that were extensively trained to respond for food reinforcers. Gene silencing caused mice to abandon goal-seeking strategies, unmasking habit-based behaviors that were propelled by interactions with the nucleus accumbens. Thus, PI3K control of goal-directed action strategies appears to act in accordance with an inverted U-shaped function, with "too much" (following cocaine) or "too little" (following p110ß subunit silencing) obstructing goal seeking and causing mice to defer to habit-like response sequences.
Assuntos
Cocaína , Fosfatidilinositol 3-Quinases , Camundongos , Animais , Estudos Prospectivos , Cocaína/farmacologia , Recompensa , Córtex Pré-Frontal/fisiologiaRESUMO
An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action-outcome expectations. In a separate experiment, we blocked action-outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action-outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences.SIGNIFICANCE STATEMENT Navigating a changing environment requires associating actions with their likely outcomes and updating these associations when they change. Dendritic spine plasticity is likely involved, yet relationships are unconfirmed. Using behavioral, chemogenetic, and viral-mediated gene silencing strategies and high-resolution microscopy, we find that modifying action-outcome expectations is associated with fewer immature spines and a greater proportion of mature spines in the ventrolateral orbitofrontal cortex (OFC). Given that the OFC is involved in prospectively calculating the likely outcomes of one's behavior, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for maintaining durable expectations.
Assuntos
Antecipação Psicológica/fisiologia , Espinhas Dendríticas/fisiologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Animais , Condicionamento Operante , Tomada de Decisões , Espinhas Dendríticas/ultraestrutura , Dependovirus/genética , Comportamento Alimentar , Feminino , Proteína do X Frágil da Deficiência Intelectual/antagonistas & inibidores , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/fisiologia , Técnicas de Silenciamento de Genes , Genes Reporter , Vetores Genéticos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Optogenética , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Reforço PsicológicoRESUMO
Goal-directed action refers to selecting behaviors based on the expectation that they will be reinforced with desirable outcomes. It is typically conceptualized as opposing habit-based behaviors, which are instead supported by stimulus-response associations and insensitive to consequences. The prelimbic prefrontal cortex (PL) is positioned along the medial wall of the rodent prefrontal cortex. It is indispensable for action-outcome-driven (goal-directed) behavior, consolidating action-outcome relationships and linking contextual information with instrumental behavior. In this brief review, we will discuss the growing list of molecular factors involved in PL function. Ventral to the PL is the medial orbitofrontal cortex (mOFC). We will also summarize emerging evidence from rodents (complementing existing literature describing humans) that it too is involved in action-outcome conditioning. We describe experiments using procedures that quantify responding based on reward value, the likelihood of reinforcement, or effort requirements, touching also on experiments assessing food consumption more generally. We synthesize these findings with the argument that the mOFC is essential to goal-directed action when outcome value information is not immediately observable and must be recalled and inferred.
Assuntos
Comportamento Animal/fisiologia , Objetivos , Córtex Pré-Frontal/fisiologia , Animais , Vias Neurais/fisiologia , Recompensa , RoedoresRESUMO
Cocaine use disorder (CUD) is a significant public health issue that generates substantial personal, familial, and economic burdens. Still, there are no FDA-approved pharmacotherapies for CUD. Cocaine-dependent individuals report anxiety during withdrawal, and alleviation of anxiety and other negative affective states may be critical for maintaining drug abstinence. However, the neurobiological mechanisms underlying abstinence-related anxiety in humans or anxiety-like behavior in rodents are not fully understood. This review summarizes investigations regarding anxiety-like behavior in mice and rats undergoing cocaine abstinence, as assessed using four of the most common anxiety-related assays: the elevated plus (or its derivative, the elevated zero) maze, open field test, light-dark transition test, and defensive burying task. We first summarize available evidence that cocaine abstinence generates anxiety-like behavior that persists throughout protracted abstinence. Then, we examine investigations concerning neuropeptide, neurotransmitter, and neuromodulator systems in cocaine abstinence-induced anxiety-like behavior. Throughout, we discuss how differences in sex, rodent strain, cocaine dose and dosing strategy and abstinence duration interact to generate anxiety-like behavior.
RESUMO
Behavioral flexibility-that is, the ability to deviate from established behavioral sequences-is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors. However, the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory remain elusive. Here we demonstrate in mice that basolateral amygdala (BLA)âOFC projections bidirectionally control memory formation when familiar behaviors are unexpectedly not rewarded, whereas OFCâdorsomedial striatum (DMS) projections facilitate memory retrieval. OFC neuronal ensembles store a memory trace for newly learned information, which appears to be facilitated by circuit-specific dendritic spine plasticity and neurotrophin signaling within defined BLA-OFC-DMS connections and obstructed by cocaine. Thus, we describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time, whereby novel memories are encoded by BLAâOFC inputs, represented within OFC ensembles and retrieved via OFCâDMS outputs during future choice.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Aprendizagem , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Corpo Estriado , Aprendizagem/fisiologia , Camundongos , Córtex Pré-Frontal/fisiologia , RecompensaRESUMO
BACKGROUND: The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts. METHODS: Here, we inhibited PI3K p110ß in the medial prefrontal cortex (mPFC) of cocaine-exposed mice. Behavioral models for studying relapse, sensitization, and decision-making biases were paired with protein quantification, RNA sequencing, and cell type-specific chemogenetic manipulation and RNA quantification to determine whether and how inhibiting PI3K p110ß confers resilience to cocaine. RESULTS: Viral-mediated PI3K p110ß silencing reduced cue-induced reinstatement of cocaine seeking by half, blocked locomotor sensitization, and restored mPFC synaptic marker content after exposure to cocaine. Cocaine blocked the ability of mice to select actions based on their consequences, and p110ß inhibition restored this ability. Silencing dopamine D2 receptor-expressing excitatory mPFC neurons mimicked cocaine, impairing goal-seeking behavior, and again, p110ß inhibition restored goal-oriented action. We verified the presence of p110ß in mPFC neurons projecting to the dorsal striatum and orbitofrontal cortex and found that inhibiting p110ß in the mPFC altered the expression of functionally defined gene clusters within the dorsal striatum and not orbitofrontal cortex. CONCLUSIONS: Subunit-selective PI3K silencing potently mitigates drug seeking, sensitization, and decision-making biases after exposure to cocaine. We suggest that inhibiting PI3K p110ß provides neuroprotection against cocaine by triggering coordinated corticostriatal adaptations.