Teneurin C-terminal associated peptide (TCAP)-1 attenuates the development and expression of naloxone-precipitated morphine withdrawal in male Swiss Webster mice.

RATIONALE: Corticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined. OBJECTIVE: To determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice. METHODS: Mice were administered via subcutaneous route TCAP-1 either before or after initial morphine exposure, after which jumping behavior was quantified to assess the effects of TCAP-1 on naloxone-precipitated morphine withdrawal. As a comparison, mice were treated with nonpeptide CRF1 receptor antagonist CP-154,526. In one experiment, plasma corticosterone (CORT) was also measured as a physiological stress indicator. RESULTS: Pretreatment with TCAP-1 (10-250 nmol/kg) before morphine treatment significantly inhibited the development of naloxone-precipitated withdrawal. TCAP-1 (250-500 nmol/kg) treatment administered after morphine treatment attenuated the behavioral expression of naloxone-precipitated withdrawal. TCAP-1 (250 nmol/kg) treatment during morphine treatment was more effective than the optimal dosing of CP-154,526 (20 mg/kg) at suppressing the behavioral expression of naloxone-precipitated withdrawal, despite similar reduction of withdrawal-induced plasma CORT level increases. CONCLUSIONS: These findings establish TCAP-1 as a potential therapeutic candidate for the prevention and treatment of morphine withdrawal.

Clinical outcomes and tumor microenvironment response to radiofrequency ablation therapy: a systematic review and meta-analysis.

Background: Radiofrequency ablation (RFA) utilizes minimally invasive high-energy current to precisely ablate tumor cells. It has been utilized in many cancer types including thyroid, lung, and liver cancer. It has been shown to provide adequate ablative margins with minimal complications; however, incomplete RFA may lead to recurrence of tumor. The underlying cellular mechanism and behavior of ablated cancer tissue is poorly understood. Methods: A systematic review was performed, searching EMBASE, Web of Science, PubMed, and Scopus for studies published up to March 2022 and reported following PRISMA guidelines. Collection was performed by two groups of investigators to avoid risk of bias. The Cochrane Collaboration's tool was used for assessing risk of bias. We identified human, in vivo, and in vitro research studies utilizing RFA for tumor tissues. We required that the studies included at least one of the following: complications, recurrence, or survival, and took interest to studies identifying cellular signaling pathway patterns after RFA. Descriptive statistical analysis was performed in 'R' software including mean and confidence interval. Results: The most frequent cancers studied were liver and lung cancers accounting for 57.4% (N=995) and 15.4% (N=267), followed by esophageal (N=190) and breast cancer (N=134). The most common reported complications were bleeding (19%) and post-operative pain (14%). In our literature search, four independent studies showed upregulation and activation of the VEGF pathway following RFA, four showed upregulation and activation of the AKT pathway following RFA, three studies demonstrated involvement of matrix metalloproteinases, and four showed upregulation of c-Met protein following RFA. Conclusions: In our review and meta-analysis, we identify several proteins and pathways of interest of which are important in wound healing, angiogenesis, and cellular growth and survival. These proteins and pathways of interest may implicate areas of research towards RFA resistance and cancer recurrence.

Dopaminergic prediction errors in the ventral tegmental area reflect a multithreaded predictive model.

Dopamine neuron activity is tied to the prediction error in temporal difference reinforcement learning models. These models make significant simplifying assumptions, particularly with regard to the structure of the predictions fed into the dopamine neurons, which consist of a single chain of timepoint states. Although this predictive structure can explain error signals observed in many studies, it cannot cope with settings where subjects might infer multiple independent events and outcomes. In the present study, we recorded dopamine neurons in the ventral tegmental area in such a setting to test the validity of the single-stream assumption. Rats were trained in an odor-based choice task, in which the timing and identity of one of several rewards delivered in each trial changed across trial blocks. This design revealed an error signaling pattern that requires the dopamine neurons to access and update multiple independent predictive streams reflecting the subject's belief about timing and potentially unique identities of expected rewards.

Molecular Targets of Triple-Negative Breast Cancer: Where Do We Stand?

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future.

Spatial Representations in Rat Orbitofrontal Cortex.

The orbitofrontal cortex (OFC) and hippocampus share striking cognitive and functional similarities. As a result, both structures have been proposed to encode "cognitive maps" that provide useful scaffolds for planning complex behaviors. However, while this function has been exemplified by spatial coding in neurons of hippocampal regions-particularly place and grid cells-spatial representations in the OFC have been investigated far less. Here we sought to address this by recording OFC neurons from male rats engaged in an open-field foraging task like that originally developed to characterize place fields in rodent hippocampal neurons. Single-unit activity was recorded as rats searched for food pellets scattered randomly throughout a large enclosure. In some sessions, particular flavors of food occurred more frequently in particular parts of the enclosure; in others, only a single flavor was used. OFC neurons showed spatially localized firing fields in both conditions, and representations changed between flavored and unflavored foraging periods in a manner reminiscent of remapping in the hippocampus. Compared with hippocampal recordings taken under similar behavioral conditions, OFC spatial representations were less temporally reliable, and there was no significant evidence of grid tuning in OFC neurons. These data confirm that OFC neurons show spatial firing fields in a large, two-dimensional environment in a manner similar to hippocampus. Consistent with the focus of the OFC on biological meaning and goals, spatial coding was weaker than in hippocampus and influenced by outcome identity.SIGNIFICANCE STATEMENT The orbitofrontal cortex (OFC) and hippocampus have both been proposed to encode "cognitive maps" that provide useful scaffolds for planning complex behaviors. This function is exemplified by place and grid cells identified in hippocampus, the activity of which maps spatial environments. The current study directly demonstrates very similar, though not identical, spatial representatives in OFC neurons, confirming that OFC-like hippocampus-can represent a spatial map under the appropriate experimental conditions.

Past experience shapes the neural circuits recruited for future learning.

Experimental research controls for past experience, yet prior experience influences how we learn. Here, we tested whether we could recruit a neural population that usually encodes rewards to encode aversive events. Specifically, we found that GABAergic neurons in the lateral hypothalamus (LH) were not involved in learning about fear in naïve rats. However, if these rats had prior experience with rewards, LH GABAergic neurons became important for learning about fear. Interestingly, inhibition of these neurons paradoxically enhanced learning about neutral sensory information, regardless of prior experience, suggesting that LH GABAergic neurons normally oppose learning about irrelevant information. These experiments suggest that prior experience shapes the neural circuits recruited for future learning in a highly specific manner, reopening the neural boundaries we have drawn for learning of particular types of information from work in naïve subjects.

Prior Cocaine Use Alters the Normal Evolution of Information Coding in Striatal Ensembles during Value-Guided Decision-Making.

Substance use disorders (SUDs) are characterized by maladaptive behavior. The ability to properly adjust behavior according to changes in environmental contingencies necessitates the interlacing of existing memories with updated information. This can be achieved by assigning learning in different contexts to compartmentalized "states." Though not often framed this way, the maladaptive behavior observed in individuals with SUDs may result from a failure to properly encode states because of drug-induced neural alterations. Previous studies found that the dorsomedial striatum (DMS) is important for behavioral flexibility and state encoding, suggesting the DMS may be an important substrate for these effects. Here, we recorded DMS neural activity in cocaine-experienced male rats during a decision-making task where blocks of trials represented distinct states to probe whether the encoding of state and state-related information is affected by prior drug exposure. We found that DMS medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) encoded such information and that prior cocaine experience disrupted the evolution of representations both within trials and across recording sessions. Specifically, DMS MSNs and FSIs from cocaine-experienced rats demonstrated higher classification accuracy of trial-specific rules, defined by response direction and value, compared with those drawn from sucrose-experienced rats, and these overly strengthened trial-type representations were related to slower switching behavior and reaction times. These data show that prior cocaine experience paradoxically increases the encoding of state-specific information and rules in the DMS and suggest a model in which abnormally specific and persistent representation of rules throughout trials in DMS slows value-based decision-making in well trained subjects.SIGNIFICANCE STATEMENT Substance use disorders (SUDs) may result from a failure to properly encode rules guiding situationally appropriate behavior. The dorsomedial striatum (DMS) is thought to be important for such behavioral flexibility and encoding that defines the situation or "state." This suggests that the DMS may be an important substrate for the maladaptive behavior observed in SUDs. In the current study, we show that prior cocaine experience results in over-encoding of state-specific information and rules in the DMS, which may impair normal adaptive decision-making in the task, akin to what is observed in SUDs.

Dopamine transients do not act as model-free prediction errors during associative learning.

Dopamine neurons are proposed to signal the reward prediction error in model-free reinforcement learning algorithms. This term represents the unpredicted or 'excess' value of the rewarding event, value that is then added to the intrinsic value of any antecedent cues, contexts or events. To support this proposal, proponents cite evidence that artificially-induced dopamine transients cause lasting changes in behavior. Yet these studies do not generally assess learning under conditions where an endogenous prediction error would occur. Here, to address this, we conducted three experiments where we optogenetically activated dopamine neurons while rats were learning associative relationships, both with and without reward. In each experiment, the antecedent cues failed to acquire value and instead entered into associations with the later events, whether valueless cues or valued rewards. These results show that in learning situations appropriate for the appearance of a prediction error, dopamine transients support associative, rather than model-free, learning.

A novel role for the actin-binding protein drebrin in regulating opiate addiction.

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.

Author Correction: Dopamine transients are sufficient and necessary for acquisition of model-based associations.

In the version of this article initially published, the laser activation at the start of cue X in experiment 1 was described in the first paragraph of the Results and in the third paragraph of the Experiment 1 section of the Methods as lasting 2 s; in fact, it lasted only 1 s. The error has been corrected in the HTML and PDF versions of the article.

Dopamine transients are sufficient and necessary for acquisition of model-based associations.

Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior.

BACKGROUND: Drug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that the transcription factor SMAD3 is increased after 7 days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here, we examined the possible interaction of BRG1-also known as SMARCA4, an adenosine triphosphatase-containing chromatin remodeler-and SMAD3 in response to cocaine exposure. METHODS: The expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using western blotting, co-immunoprecipitation, and chromatin immunoprecipitation following abstinence from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors after either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1. RESULTS: After withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, whereas viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior. CONCLUSIONS: BRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity that mediates cocaine seeking after a period of withdrawal.

DISC1 signaling in cocaine addiction: Towards molecular mechanisms of co-morbidity.

Substance abuse and other psychiatric diseases may share molecular pathology. In order to test this hypothesis, we examined the role of Disrupted In Schizophrenia 1 (DISC1), a psychiatric risk factor, in cocaine self-administration (SA). Cocaine SA significantly increased expression of DISC1 in the nucleus accumbens (NAc); while knockdown of DISC1 in NAc significantly increased cocaine SA and decreased phosphorylation of GSK-3ß at Ser9 compared to scrambled shRNA. Our study provides the first mechanistic evidence of a critical role of DISC1 in drug-induced behavioral neuroadaptations and sheds more light at the shared molecular pathology of drug abuse and other major psychiatric disorders.

Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity.

Activin receptor signaling, including the transcription factor Smad3, was upregulated in the rat nucleus accumbens (NAc) shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. Thus, Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self-administration.

Elevated potassium provides an ionic mechanism for deep brain stimulation in the hemiparkinsonian rat.

The mechanism of high-frequency stimulation used in deep brain stimulation (DBS) for Parkinson's disease (PD) has not been completely elucidated. Previously, high-frequency stimulation of the rat entopeduncular nucleus, a basal ganglia output nucleus, elicited an increase in [K(+)](e) to 18 mm, in vitro. In this study, we assessed whether elevated K(+) can elicit DBS-like therapeutic effects in hemiparkinsonian rats by employing the limb-use asymmetry test and the self-adjusting stepping test. We then identified how these effects were meditated with in-vivo and in-vitro electrophysiology. Forelimb akinesia improved in hemiparkinsonian rats undergoing both tests after 20 mm KCl injection into the substantia nigra pars reticulata (SNr) or the subthalamic nucleus. In the SNr, neuronal spiking activity decreased from 38.2 ± 1.2 to 14.6 ± 1.6 Hz and attenuated SNr beta-frequency (12-30 Hz) oscillations after K(+) treatment. These oscillations are commonly associated with akinesia/bradykinesia in patients with PD and animal models of PD. Pressure ejection of 20 mm KCl onto SNr neurons in vitro caused a depolarisation block and sustained quiescence of SNr activity. In conclusion, our data showed that elevated K(+) injection into the hemiparkinsonian rat SNr improved forelimb akinesia, which coincided with a decrease in SNr neuronal spiking activity and desynchronised activity in SNr beta frequency, and subsequently an overall increase in ventral medial thalamic neuronal activity. Moreover, these findings also suggest that elevated K(+) may provide an ionic mechanism that can contribute to the therapeutic effects of DBS for the motor treatment of advanced PD.