Local and global predictors of synapse elimination during motor learning.

During learning, synaptic connections between excitatory neurons in the brain display considerable dynamism, with new connections being added and old connections eliminated. Synapse elimination offers an opportunity to understand the features of synapses that the brain deems dispensable. However, with limited observations of synaptic activity and plasticity in vivo, the features of synapses subjected to elimination remain poorly understood. Here, we examined the functional basis of synapse elimination in the apical dendrites of L2/3 neurons in the primary motor cortex throughout motor learning. We found no evidence that synapse elimination is facilitated by a lack of activity or other local forms of plasticity. Instead, eliminated synapses display asynchronous activity with nearby synapses, suggesting that functional synaptic clustering is a critical component of synapse survival. In addition, eliminated synapses show delayed activity timing with respect to postsynaptic output. Thus, synaptic inputs that fail to be co-active with their neighboring synapses or are mistimed with neuronal output are targeted for elimination.

Exploring the Types of Social Support Exchanged by Survivors of Pediatric Stroke and Their Families in an Online Peer Support Community: Qualitative Thematic Analysis.

BACKGROUND: Pediatric stroke is relatively rare and underresearched, and there is little awareness of its occurrence in wider society. There is a paucity of literature on the effectiveness of interventions to improve rehabilitation and the services available to survivors. Access to online health communities through the internet may be a means of support for patients with pediatric stroke and their families during recovery; however, little research has been done in this area. OBJECTIVE: This study aims to identify the types of social support provided by an online peer support group to survivors of pediatric stroke and their families. METHODS: This was a qualitative thematic analysis of posts from a pediatric stroke population on a UK online stroke community active between 2004 and 2011. The population was split into 2 groups based on whether stroke survivors were aged ≤18 years or aged >18 years at the time of posting. The posts were read by 2 authors who used the adapted Social Support Behavior Code to analyze the types of social support exchanged. RESULTS: A total of 52 participants who experienced a pediatric stroke were identified, who posted a total of 425 messages to the community. About 41 survivors were aged ≤18 years at the time of posting and were written about by others (31/35 were mothers), while 11 were aged >18 years and were writing about themselves. Survivors and their families joined together in discussion threads. Support was offered and received by all participants, regardless of age. Of all 425 posts, 193 (45.4%) contained at least 1 instance of social support. All 5 types of social support were identified: informational, emotional, network, esteem support, and tangible aid. Informational and emotional support were most commonly exchanged. Emotional support was offered more often than informational support among participants aged ≤18 years at the time of posting; this finding was reversed in the group aged >18 years. Network support and esteem support were less commonly exchanged. Notably, the access subcategory of network support was not exchanged with the community. Tangible aid was the least commonly offered type of support. The exchanged social support provided insight into rehabilitation interventions and the unmet needs of pediatric stroke survivors. CONCLUSIONS: We found evidence of engagement of childhood stroke survivors and their families in an online stroke community, with peer support being exchanged between both long- and short-term survivors of pediatric stroke. Engagement of long-term survivors of pediatric stroke through the online community was key, as they were able to offer informational support from lived experience. Further interventional research is needed to assess health and rehabilitation outcomes from engagement with online support groups. Research is also needed to ensure safe, nurturing online communities.

CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use.

BACKGROUND: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice. METHODS: To investigate the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. RESULTS: We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. CONCLUSIONS: Together, these findings point to the CREB-Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine.

Silent Synapses in Cocaine-Associated Memory and Beyond.

Glutamatergic synapses are key cellular sites where cocaine experience creates memory traces that subsequently promote cocaine craving and seeking. In addition to making across-the-board synaptic adaptations, cocaine experience also generates a discrete population of new synapses that selectively encode cocaine memories. These new synapses are glutamatergic synapses that lack functionally stable AMPARs, often referred to as AMPAR-silent synapses or, simply, silent synapses. They are generated de novo in the NAc by cocaine experience. After drug withdrawal, some of these synapses mature by recruiting AMPARs, contributing to the consolidation of cocaine-associated memory. After cue-induced retrieval of cocaine memories, matured silent synapses alternate between two dynamic states (AMPAR-absent vs AMPAR-containing) that correspond with the behavioral manifestations of destabilization and reconsolidation of these memories. Here, we review the molecular mechanisms underlying silent synapse dynamics during behavior, discuss their contributions to circuit remodeling, and analyze their role in cocaine-memory-driven behaviors. We also propose several mechanisms through which silent synapses can form neuronal ensembles as well as cross-region circuit engrams for cocaine-specific behaviors. These perspectives lead to our hypothesis that cocaine-generated silent synapses stand as a distinct set of synaptic substrates encoding key aspects of cocaine memory that drive cocaine relapse.

Nucleus accumbens fast-spiking interneurons in motivational and addictive behaviors.

The development of drug addiction is associated with functional adaptations within the reward circuitry, within which the nucleus accumbens (NAc) is anatomically positioned as an interface between motivational salience and behavioral output. The functional output of NAc is profoundly altered after exposure to drugs of abuse, and some of the functional changes continue to evolve during drug abstinence, contributing to numerous emotional and motivational alterations related drug taking, seeking, and relapse. As in most brain regions, the functional output of NAc is critically dependent on the dynamic interaction between excitation and inhibition. One of the most prominent sources of inhibition within the NAc arises from fast-spiking interneurons (FSIs). Each NAc FSI innervates hundreds of principal neurons, and orchestrates population activity through its powerful and sustained feedforward inhibition. While the role of NAc FSIs in the context of drug addiction remains poorly understood, emerging evidence suggests that FSIs and FSI-mediated local circuits are key targets for drugs of abuse to tilt the functional output of NAc toward a motivational state favoring drug seeking and relapse. In this review, we discuss recent findings and our conceptualization about NAc FSI-mediated regulation of motivated and cocaine-induced behaviors. We hope that the conceptual framework proposed in this review may provide a useful guidance for ongoing and future studies to determine how FSIs influence the function of NAc and related reward circuits, ultimately leading to addictive behaviors.

Psychostimulant-Induced Adaptations in Nucleus Accumbens Glutamatergic Transmission.

Carrying different aspects of emotional and motivational signals, glutamatergic synaptic projections from multiple limbic and paralimbic brain regions converge to the nucleus accumbens (NAc), in which these arousing signals are processed and prioritized for behavioral output. In animal models of drug addiction, some key drug-induced alterations at NAc glutamatergic synapses underlie important cellular and circuit mechanisms that promote subsequent drug taking, seeking, and relapse. With the focus of cocaine, we review changes at NAc glutamatergic synapses that occur after different drug procedures and abstinence durations, and the behavioral impact of these changes.

Silent synapses dictate cocaine memory destabilization and reconsolidation.

Cocaine-associated memories are persistent, but, on retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, on memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 h later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are timed by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption.

Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.

Understanding the transcriptional changes that are engaged in stress resilience may reveal novel antidepressant targets. Here we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB-Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in prefrontal cortex neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB-Zfp189 interactions in mediating a central transcriptional network of resilience.

Feasibility of a Telehealth Educational Program on Self-Management of Pain and Fatigue in Adult Cancer Patients.

CONTEXT: Pain and fatigue are common symptoms among cancer patients and often lead to substantial distress. Innovative self-management programs for pain and fatigue are needed. OBJECTIVES: The primary objective was to assess the feasibility of a telehealth pain and fatigue self-management program among adult cancer patients. Secondary objectives included assessment of differences in patient characteristics, recruitment, and retention of patients based on two screening strategies: 1) navigator-collected, patient-reported pain or fatigue and 2) in-clinic, physician-identified pain or fatigue. METHODS: This prospective, nonrandomized, pre-post evaluation assessed feasibility, which was defined as 50% of eligible patients choosing to participate and completing the intervention. Patient demographics and patient-reported outcomes (patient activation, distress, symptoms, and quality of life) were collected at baseline and study completion. Differences in baseline characteristics were compared between cohorts and for patients who did vs. did not graduate from the program. RESULTS: The program did not meet feasibility requirements because of only 34% of eligible patients choosing to participate. However, 50% of patients starting the program graduated. Differences in baseline characteristics and retention rates were noted by recruitment strategy. At baseline, 27.3% of navigated patients were at the highest activation level compared with 7.1% in the physician-referred, non-navigated patients (P = 0.17); more than 15% of non-completers were at the lowest activation level compared with 9% of completers (P = 0.85). CONCLUSION: Telehealth self-management program for pain and fatigue may be better accepted among selected segments of cancer patients. Larger scale studies are needed to assess the efficacy of this program in a more selective activated population.

A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens.

The nucleus accumbens (NAc) gates motivated behaviors through the functional output of principle medium spiny neurons (MSNs), whereas dysfunctional output of NAc MSNs contributes to a variety of psychiatric disorders. Fast-spiking interneurons (FSIs) are sparsely distributed throughout the NAc, forming local feedforward inhibitory circuits. It remains elusive how FSI-based feedforward circuits regulate the output of NAc MSNs. Here, we investigated a distinct subpopulation of NAc FSIs that express the cannabinoid receptor type-1 (CB1). Using a combination of paired electrophysiological recordings and pharmacological approaches, we characterized and compared feedforward inhibition of NAc MSNs from CB1+ FSIs and lateral inhibition from recurrent MSN collaterals. We observed that CB1+ FSIs exerted robust inhibitory control over a large percentage of nearby MSNs in contrast to local MSN collaterals that provided only sparse and weak inhibitory input to their neighboring MSNs. Furthermore, CB1+ FSI-mediated feedforward inhibition was preferentially suppressed by endocannabinoid (eCB) signaling, whereas MSN-mediated lateral inhibition was unaffected. Finally, we demonstrated that CB1+ FSI synapses onto MSNs are capable of undergoing experience-dependent long-term depression in a voltage- and eCB-dependent manner. These findings demonstrated that CB1+ FSIs are a major source of local inhibitory control of MSNs and a critical component of the feedforward inhibitory circuits regulating the output of the NAc.

Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses.

Exposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. In an effort to explain this paradox, we found that both drugs induced NMDA receptor-containing, AMPA receptor-silent excitatory synapses, albeit in distinct cell types through opposing cellular mechanisms. Cocaine selectively induced silent synapses in D1-type neurons, likely via a synaptogenesis process, whereas morphine induced silent synapses in D2-type neurons via internalization of AMPA receptors from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses became 'unsilenced' by recruiting AMPA receptors to strengthen excitatory inputs to D1-type neurons, whereas morphine-generated silent synapses were likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell type-specific, opposing mechanisms produced the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs.