Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the precise neural mechanisms ...underlying the development of depression remain elusive. Although it is impossible to phenocopy every symptom of human depression in rodents, the preclinical field has had great success in modeling some of the core affective and neurovegetative depressive symptoms, including social withdrawal, anhedonia, and weight loss. Adaptations in select cell populations may underlie these individual depressive symptoms and new tools have expanded our ability to monitor and manipulate specific cell types. This review outlines some of the most recent preclinical discoveries on the molecular and neurophysiological mechanisms in reward circuitry that underlie the expression of behavioral constructs relevant to depressive symptoms.
Addiction is a disorder of behavioral symptoms including enhanced incentive salience of drug-associated cues, but also a negative affective state. Cocaine-evoked synaptic plasticity in the reward ...system, particularly the nucleus accumbens (NAc), drives drug-adaptive behavior. However, how information is integrated downstream of the NAc remains unclear. Here, we identify the ventral pallidum (VP) as a site of convergence of medium spiny neurons expressing dopamine (DA) receptor type 1 (D1-MSNs) and type 2 (D2-MSNs) of the NAc. Repeated in vivo cocaine exposure potentiated output of D1-MSNs, but weakened output of D2-MSNs, occluding LTP and LTD at these synapses, respectively. Selectively restoring basal transmission at D1-MSN-to-VP synapses abolished locomotor sensitization, whereas restoring transmission at D2-MSN-to-VP synapses normalized motivational deficits. Our results support a model by which drug-evoked synaptic plasticity in the VP mediates opposing behavioral symptoms; targeting the VP may provide novel therapeutic strategies for addictive disorders.
•The ventral pallidum (VP) integrates inputs from D1- and D2-MSNs from the NAc•Cocaine exposure potentiates output of D1-MSNs and depresses output of D2-MSNs to the VP•Plasticity at D1-MSN-to-VP synapses is implicated in behavioral sensitization to cocaine•Plasticity at D2-MSN-to-VP synapses contributes to cocaine-induced negative affect
Creed et al. identify distinct forms of plasticity between D1- and D2-MSNs and the ventral pallidum. Cocaine exposure occluded activity-dependent LTP and LTD at D1-VP and D2-VP synapses. Transmission at these synapses mediates distinct behavioral symptoms of addiction.
Highlights ► Cocaine-induced adaptations in nucleus accumbens (NAc) contribute to relapse. ► Projection neurons in NAc are D1 or D2 dopamine receptor-expressing. ► D1 and D2 cell types in NAc are not ...synonymous with direct/indirect pathways. ► NAc neurons show cocaine-induced changes in synaptic plasticity. ► New technologies examine involvement of D1 and/or D2 projection neurons.
The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, ...are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward.
The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and ...nucleus accumbens (ventral striatum). Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum's two major subtypes of medium spiny neurons (MSNs) in drug addiction remained elusive. Recent advances in cell-type-specific technologies, including fluorescent reporter mice, transgenic, or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction.
Protracted social isolation of adult mice induced behavioral, transcriptional and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC) and impaired adult myelination. Social ...re-integration was sufficient to normalize behavioral and transcriptional changes. Short periods of isolation affected chromatin and myelin, but did not induce behavioral changes. Thus, myelinating oligodendrocytes in the adult PFC respond to social interaction with chromatin changes, suggesting that myelination acts as a form of adult plasticity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Immediate early genes (IEGs) were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these ...neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN) subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior.
Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, ...we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.
► Cocaine exposure enhances vulnerability to chronic social stress ► Histone H3 dimethylation in nucleus accumbens links cocaine to stress vulnerability ► G9a overexpression in NAc after repeated cocaine protects mice from social stress ► Resilience to stress via repression of BDNF-TrkB-CREB signaling
Nucleus accumbens dopamine 1 receptor medium spiny neurons (D1-MSNs) play a critical role in the development of depression-like behavior in mice. Social defeat stress causes dendritic morphological ...changes on this MSN subtype through expression and activation of early growth response 3 (EGR3) and the Rho guanosine triphosphatase RhoA. However, it is unknown how RhoA inhibition affects electrophysiological properties underlying stress-induced susceptibility.
A novel RhoA-specific inhibitor, Rhosin, was used to inhibit RhoA activity following chronic social defeat stress. Whole-cell electrophysiological recordings of D1-MSNs were performed to assess synaptic and intrinsic consequences of Rhosin treatment on stressed mice. Additionally, recorded cells were filled and analyzed for their morphological properties.
We found that RhoA inhibition prevents both D1-MSN hyperexcitability and reduced excitatory input to D1-MSNs caused by social defeat stress. Nucleus accumbens–specific RhoA inhibition is capable of blocking susceptibility caused by D1-MSN EGR3 expression. Lastly, we found that Rhosin enhances spine density, which correlates with D1-MSN excitability, without affecting overall dendritic branching.
These findings demonstrate that pharmacological inhibition of RhoA during stress drives an enhancement of total spine number in a subset of nucleus accumbens neurons that prevents stress-related electrophysiological deficits and promotes stress resiliency.
Stress alters the structure and function of brain reward circuitry and is an important risk factor for developing depression. In the nucleus accumbens (NAc), structural and physiological plasticity ...of medium spiny neurons (MSNs) have been linked to increased stress-related and depression-like behaviors. NAc MSNs have opposing roles in driving stress-related behaviors that is dependent on their dopamine receptor expression. After chronic social defeat stress, NAc MSNs exhibit increased dendritic spine density. However, it remains unclear if the dendritic spine plasticity is MSN subtype specific. Here we use viral labeling to characterize dendritic spine morphology specifically in dopamine D2 receptor expressing MSNs (D2-MSNs). After chronic social defeat, D2-MSNs exhibit increased spine density that is correlated with enhanced social avoidance behavior. Together, our data indicate dendritic spine plasticity is MSN subtype specific, improving our understanding of structural plasticity after chronic stress.
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