At the core of value-based learning is the nucleus accumbens (NAc). D1- and D2-receptor-containing medium spiny neurons (MSNs) in the NAc core are hypothesized to have opposing valence-based roles in behavior. Using optical imaging and manipulation approaches in mice, we show that neither D1 nor D2 MSNs signal valence.
View Article and Find Full Text PDFDopamine release in the nucleus accumbens (NAc) is causally linked to adaptive aversive learning, and its dysregulation is a core phenotype in anxiety and stress disorders. Here, we record NAc core dopamine during a task where mice learn to discriminate between cues signaling two types of outcomes: (1) footshock presentation and (2) footshock omission. We show that dopamine release is evoked by footshock omission.
View Article and Find Full Text PDFEmpathy is the ability to adopt others' sensory and emotional states and is an evolutionarily conserved trait among mammals. In rodents, empathy manifests itself as social modulation of aversive stimuli such as acknowledging and acting on conspecifics' distress. The neuronal network underlying social transmission of information is known to overlap with the brain regions that mediate behavioral responses to aversive and rewarding stimuli.
View Article and Find Full Text PDFStudies investigating the neural mechanisms by which associations between cues and predicted outcomes control behavior often use associative learning frameworks to understand the neural control of behavior. These frameworks do not always account for the full range of effects that novelty can have on behavior and future associative learning. Here, in mice, we show that dopamine in the nucleus accumbens core is evoked by novel, neutral stimuli, and the trajectory of this response over time tracked habituation to these stimuli.
View Article and Find Full Text PDFA large body of work has aimed to define the precise information encoded by dopaminergic projections innervating the nucleus accumbens (NAc). Prevailing models are based on reward prediction error (RPE) theory, in which dopamine updates associations between rewards and predictive cues by encoding perceived errors between predictions and outcomes. However, RPE cannot describe multiple phenomena to which dopamine is inextricably linked, such as behavior driven by aversive and neutral stimuli.
View Article and Find Full Text PDFCognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning.
View Article and Find Full Text PDFMicroglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures.
View Article and Find Full Text PDFA large body of work has focused on understanding stimulus-driven behavior, sex differences in these processes, and the neural circuits underlying them. Many preclinical mouse models present rewarding or aversive stimuli in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes. In addition, the context (or reinforcement schedule under) in which stimuli are encountered can engender different behavioral responses to the same stimulus.
View Article and Find Full Text PDFNicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring.
View Article and Find Full Text PDFCognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.
View Article and Find Full Text PDFWhile preclinical work has aimed to outline the neural mechanisms of drug addiction, it has overwhelmingly focused on male subjects. There has been a push in recent years to incorporate females into existing addiction models; however, males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction. Traditional self-administration models often include light or tone cues that serve as discriminative stimuli and/or consequent stimuli, making it nearly impossible to disentangle the effects of cue learning, the cues themselves, and acute effects of psychostimulant drugs.
View Article and Find Full Text PDFCocaine addiction is characterized by aberrant plasticity of the mesolimbic dopamine circuit, leading to dysregulation of motivation to seek and take drug. Despite the significant toll that cocaine use disorder exacts on society, there are currently no available pharmacotherapies. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a soluble cytokine that alters the behavioral response to cocaine and which increases dopamine release from the ventral tegmental area (VTA).
View Article and Find Full Text PDFNumerous studies have attributed the psychopathology of anxiety and stress disorders to maladaptive behavioral responses such as an inability to extinguish fear. Therefore, understanding neural substrates of fear extinction is imperative for developing more effective therapies for anxiety and stress disorders. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs in the fear extinction process.
View Article and Find Full Text PDFDeficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition.
View Article and Find Full Text PDFStress and anxiety disorders such as posttraumatic stress disorder (PTSD) are characterized by disrupted safety learning. Tobacco smoking has been strongly implicated in stress and anxiety disorder symptomatology, both as a contributing factor and as a vulnerability factor. Rodent studies from our lab have recently shown that acute and chronic nicotine exposure disrupts safety learning.
View Article and Find Full Text PDFAnxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown.
View Article and Find Full Text PDFRationale: Numerous studies have attributed the psychopathology of post-traumatic stress disorder (PTSD) to maladaptive behavioral responses such as an inability to extinguish fear. While exposure therapies are mostly effective in treating these disorders by enhancing extinction learning, relapse of PTSD symptoms is common. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs to fear extinction OBJECTIVES: In the present study, we examined the effects of inhibition and desensitization of α4β2 nAChRs via a full antagonist (Dihydro-beta-erythroidine (DhβE)) and two α4β2 nAChR partial-agonists (varenicline and sazetidine-A) on contextual fear extinction, locomotor activity, and spontaneous recovery of contextual fear in mice.
View Article and Find Full Text PDFPost-traumatic stress disorder (PTSD) is a devastating disorder with symptoms such as flashbacks, hyperarousal, and avoidance of reminders of the traumatic event. Exposure therapy, which attempts to extinguish fear responses, is a commonly used treatment for PTSD but relapse following successful exposure therapy is a frequent problem. In rodents, spontaneous recovery (SR), where extinguished fear responses resurface following extinction treatment, is used as a model of fear relapse.
View Article and Find Full Text PDFPharmacol Biochem Behav
February 2018
Anxiety and stress disorders occur at a higher rate in women compared to men as well as in smokers in comparison to non-smoker population. Nicotine is known to impair fear extinction, which is altered in anxiety disorders. However, nicotine differentially affects fear learning in men and women, which may mean that sex and nicotine-product use can interact to also alter fear extinction.
View Article and Find Full Text PDFPrevious research has shown that acute nicotine, an agonist of nAChRs, impaired fear extinction. However, the effects of acute nicotine on consolidation of contextual fear extinction memories and associated cell signaling cascades are unknown. Therefore, we examined the effects of acute nicotine injections before (pre-extinction) and after (post-extinction) contextual fear extinction on behavior and the phosphorylation of dorsal and ventral hippocampal ERK1/2 and JNK1 and protein levels on the 1st and 3rd day of extinction.
View Article and Find Full Text PDFCurr Neuropharmacol
September 2018
Background: Nicotine exposure affects the hippocampus through activation of hippocampal nicotinic acetylcholine receptors (nAChRs), which are present throughout excitatory and inhibitory hippocampal circuitry. The role of cholinergic functioning in the hippocampus varies across developmental stages so that nicotine exposure differentially affects this region depending upon timing of exposure, producing developmentally distinct changes in structure, function, and behavior.
Methods: We synthesize findings across literature in this area to comprehensively review current understanding of the unique effects of nicotine exposure on the hippocampus throughout the lifespan with a focus on hippocampal morphology, cholinergic functioning, and hippocampusdependent learning and memory.
Adolescence is a period of high risk for the initiation of nicotine product usage and exposure to traumatic events. In parallel, nicotine exposure has been found to age-dependently modulate acquisition of contextual fear memories; however, it is unknown if adolescent nicotine exposure alters extinction of fear related memories. Age-related differences in sensitivity to the effects of nicotine on fear extinction could increase or decrease susceptibility to anxiety disorders.
View Article and Find Full Text PDFIt has long been hypothesized that conditioning mechanisms play major roles in addiction. Specifically, the associations between rewarding properties of drugs of abuse and the drug context can contribute to future use and facilitate the transition from initial drug use into drug dependency. On the other hand, the self-medication hypothesis of drug abuse suggests that negative consequences of drug withdrawal result in relapse to drug use as an attempt to alleviate the negative symptoms.
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