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Economic stress can serve as a second hit for people who have already accumulated a history of adverse life experiences. How one recovers from a setback is a core feature of resilience but is seldom captured in animal studies. We challenged mice in a novel 2-hit stress model by first exposing them to chronic social defeat stress and then testing adaptations to increasing reward scarcity on a neuroeconomic task. Mice were tested across months on the Restaurant Row task, during which they foraged daily for their primary source of food while on a limited time budget in a closed-economy system. An abrupt transition into a reward-scarce environment elicits an economic challenge, precipitating a drop in food intake and body weight to which mice must respond to survive. We found that mice with a history of social stress mounted a robust behavioral response to this economic challenge that was achieved through a complex redistribution of time allocation among competing opportunities. Interestingly, we found that mice with a history of social defeat displayed changes in the development of decision-making policies during the recovery process that are important not only for ensuring food security necessary for survival but also prioritizing subjective value and that these changes emerged only for certain types of choices. These findings indicate that an individual's capacity to recover from economic challenges depends on that person's prior history of stress and can affect multiple decision-making aspects of subjective well-being, thus highlighting a motivational balance that may be altered in stress-related disorders such as depression. [ABSTRACT FROM AUTHOR]

A common symptom of obsessive-compulsive disorder is the persistent avoidance of cues incorrectly associated with negative outcomes. This maladaptation becomes increasingly evident as subjects fail to respond to extinction-based treatments such as exposure-with-response prevention therapy. While previous studies have highlighted the role of the insular-orbital cortex in fine-tuning avoidance-based decisions, little is known about the projections from this area that might modulate compulsive-like avoidance. Here, we used anatomical tract-tracing, single-unit recording, and optogenetics to characterize the projections from the insular-orbital cortex. To model exposure-with-response prevention and persistent avoidance in rats, we used the platform-mediated avoidance task followed by extinction-with-response prevention training. Using tract-tracing and unit recording, we found that projections from the agranular insular/lateral orbital (AI/LO) cortex to the prefrontal cortex predominantly target the rostral portion of the prelimbic (rPL) cortex and excite rPL neurons. Photoinhibiting this projection induced persistent avoidance after extinction-with-response prevention training, an effect that was still present 1 week later. Consistent with this, photoexcitation of this projection prevented persistent avoidance in overtrained rats. This projection to rPL appears to be key for AI/LO's effects, considering that there was no effect of photoinhibiting AI/LO projections to the ventral striatum or basolateral amygdala. Our findings suggest that projections from the AI/LO to the rPL decreases the likelihood of avoidance behavior following extinction. In humans, this connectivity may share some homology of projections from lateral prefrontal cortices (i.e., ventrolateral prefrontal cortex, orbitofrontal cortex, and insula) to other prefrontal areas and the anterior cingulate cortex, suggesting that reduced activity in these pathways may contribute to obsessive-compulsive disorder. [ABSTRACT FROM AUTHOR]

The article presents a study on distinct forms of regret linked to resilience versus susceptibility to stress regulated by region-specific cyclic adenosine monophosphate response element–binding protein (CREB) function. It provides information on how maladaptive stress response traits relate to forms of counterfactual thinking, which regulate mood disorders.

Objective: Neurons in PL and IL project densely to two areas implicated in active avoidance: the basolateral amygdala (BLA) and the ventral striatum (VS). We therefore combined c-Fos immunohistochemistry with retrograde tracers to characterize signaling in platform-mediated active avoidance.Methods: Male rats  were infused with retrograde tracers (CTB, FB) into basolateral amygdala and ventral striatum and conditioned to avoid tone-signaled footshocks by stepping onto a nearby platform. In a subsequent test session, rats received either 2 unreinforced tones (avoidance retrieval) or 15 unreinforced tones (avoidance extinction) followed by analysis of c-Fos combined with fluorescent imaging of retrograde tracers.Results: Retrieval of avoidance did not activate IL neurons, but did activate PL neurons projecting to BLA, and to a lesser extent VS. Extinction of avoidance activated IL neurons projecting to both BLA and VS, as well as PL neurons projecting to VS.Conclusions: Our observation that avoidance retrieval is signaled by PL projections to BLA suggests that PL may modulate VS indirectly via BLA, and agrees with other findings implicating BLA in active avoidance. Less expected was the signaling of extinction via PL inputs to VS, which may converge with IL inputs to VS to inhibit expression of avoidance. [ABSTRACT FROM AUTHOR]

The abuse of anabolic androgenic steroids (AAS) has been considered a major public health problem during decades. Supraphysiological doses of AAS may lead to a variety of neuroendocrine problems. Precisely, the hypothalamic-pituitary-gonadal (HPG) axis is one of the body systems that is mainly influenced by steroidal hormones. Fluctuations of the hormonal milieu result in alterations of reproductive function, which are made through changes in hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH). In fact, previous studies have shown that AAS modulate the activity of these neurons through steroid-sensitive afferents. To increase knowledge about the cellular mechanisms induced by AAS in GnRH neurons, we performed proteomic analyses of the murine hypothalamic GT1-7 cell line after exposure to 17α-methyltestosterone (17α-meT; 1 μM). These cells represent a good model for studying regulatory processes because they exhibit the typical characteristics of GnRH neurons, and respond to compounds that modulate GnRH in vivo. Two-dimensional difference in gel electrophoresis (2D-DIGE) and mass spectrometry analyses identified a total of 17 different proteins that were significantly affected by supraphysiological levels of AAS. Furthermore, pathway analyses showed that modulated proteins were mainly associated to glucose metabolism, drug detoxification, stress response and cell cycle. Validation of many of these proteins, such as GSTM1, ERH, GAPDH, PEBP1 and PDIA6, were confirmed by western blotting. We further demonstrated that AAS exposure decreased expression of estrogen receptors and GnRH, while two important signaling pathway proteins p-ERK, and p-p38, were modulated. Our results suggest that steroids have the capacity to directly affect the neuroendocrine system by modulating key cellular processes for the control of reproductive function. [ABSTRACT FROM AUTHOR]

Background Recent research in humans and rodents has explored the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VS) as a possible treatment for drug addiction. However, the optimum electrode placement and optimum DBS parameters have not been thoroughly studied. Here we varied stimulation sites and frequencies to determine whether DBS of the VS could facilitate the extinction of morphine-induced conditioned place preference in rats. Methods Rats were implanted with DBS electrodes in the dorsal or ventral subregions of the VS and trained to the morphine conditioned place preference. Subsequently, rats received extinction sessions over 9 days, combined with 60 min of either high- (130 Hz) or low- (20 Hz) frequency DBS. To study circuit-wide activations after DBS of the VS, c-fos immunohistochemistry was performed in regions involved in the extinction of drug-seeking behaviors. Results High-frequency DBS of the dorsal-VS impaired both extinction training and extinction memory, whereas high-frequency DBS of the ventral-VS had no effect. In contrast, low-frequency DBS of the dorsal-VS strengthened extinction memory when tested 2 or 9 days after the cessation of stimulation. Both DBS frequencies increased c-fos expression in the infralimbic prefrontal cortex, but only low-frequency DBS increased c-fos expression in the basal amygdala and the medial portion of the central amygdala. Conclusions Our results suggest that low-frequency (rather than high-frequency) DBS of the dorsal-VS strengthens extinction memory and may be a potential adjunct for extinction-based therapies for treatment-refractory opioid addiction. [ABSTRACT FROM AUTHOR]

Adolescents and adults engage in anabolic-androgenic steroid (AAS) misuse seeking their anabolic effects, even though later on, many could develop neuropsychological dependence. Previously, we have shown that nandrolone induces conditioned place preference (CPP) in adult male mice. However, whether nandrolone induces CPP during adolescence remains unknown. In this study, the CPP test was used to determine the rewarding properties of nandrolone (7.5 mg/kg) in adolescent mice. In addition, since D1 dopamine receptors (D1DR) are critical for reward-related processes, the effect of nandrolone on the expression of D1DR in the nucleus accumbens (NAc) was investigated by Western blot analysis. Similar to our previous results, nandrolone induced CPP in adults. However, in adolescents, nandrolone failed to produce place preference. At the molecular level, nandrolone decreased D1DR expression in the NAc only in adult mice. Our data suggest that nandrolone may not be rewarding in adolescents at least during short-term use. The lack of nandrolone rewarding effects in adolescents may be due, in part to differences in D1DR expression during development. [ABSTRACT FROM AUTHOR]

• Extinction learning induced Bdnf upregulation in the ventral striatum. • Extinction resistance was associated with selective gene targets. • Extinction training counteracts the withdrawal-associated plasticity. • The lack of extinction training induced a widespread modulation of genes. Persistent drug-seeking behavior has been associated with deficits in neural circuits that regulate the extinction of addictive behaviors. Although there is extensive data that associates addiction phases with neuroplasticity changes in the reward circuit, little is known about the underlying mechanisms of extinction learning of opioid associated cues. Here, we combined morphine-conditioned place preference (CPP) with real-time polymerase chain reaction (RT-PCR) to identify the effects of extinction training on the expression of genes (mRNAs) associated with synaptic plasticity and opioid receptors in the ventral striatum/nucleus accumbens (VS/NAc). Following morphine extinction training, we identified two animal subgroups showing either extinction (low CPP) or extinction-resistance (high CPP). A third group were conditioned to morphine but did not receive extinction training (sham-extinction; high CPP). RT-PCR results showed that brain derived neurotrophic factor (Bdnf) was upregulated in rats showing successful extinction. Conversely, the lack of extinction training (sham-extinction) upregulated genes associated with kinases (Camk2g), neurotrophins (Ngfr), synaptic connectivity factors (Ephb2), glutamate neurotransmission (Grm8) and opioid receptors (μ1, Δ1). To further identify genes modulated by morphine itself, comparisons with their saline-counterparts were performed. Results revealed that Bdnf was consistently upregulated in the extinction group. Alternatively, widespread gene modulation was observed in the group with lack of extinction training (i.e. Drd2, Cnr1, Creb, μ1, Δ1) and the group showing extinction resistance (i.e. Crem, Rheb, Tnfa). Together, our study builds on the identification of putative genetic markers for the extinction learning of drug-associated cues. [ABSTRACT FROM AUTHOR]

MiR-124 is a highly expressed miRNA in the brain and regulates genes involved in neuronal function. We report that miR-124 post-transcriptionally regulates PARP-1. We have identified a highly conserved binding site of miR-124 in the 3′-untranslated region (3′UTR) of Parp-1 mRNA. We demonstrate that miR-124 directly binds to the Parp-1 3′UTR and mutations in the seed sequences abrogate binding between the two RNA molecules. Luciferase reporter assay revealed that miR-124 post-transcriptionally regulates Parp-1 3′UTR activity in a dopaminergic neuronal cell model. Interestingly, the binding region of miR-124 in Parp-1 3′UTR overlapped with the target sequence of miR-125b, another post-transcriptional regulator of Parp-1. Our results from titration and pull-down studies revealed that miR-124 binds to Parp-1 3′UTR with greater affinity and confers a dominant post-transcriptional inhibition compared to miR-125b. Interestingly, acute or chronic cocaine exposure downregulated miR-124 levels concomitant with upregulation of PARP-1 protein in dopaminergic-like neuronal cells in culture. Levels of miR-124 were also downregulated upon acute or chronic cocaine exposure in the mouse nucleus accumbens (NAc)-a key reward region of brain. Time-course studies revealed that cocaine treatment persistently downregulated miR-124 in NAc. Consistent with this finding, miR-124 expression was also significantly reduced in the NAc of animals conditioned for cocaine place preference. Collectively, these studies identify Parp-1 as a direct target of miR-124 in neuronal cells, establish miR-124 as a cocaine-regulated miRNA in the mouse NAc, and highlight a novel pathway underlying the molecular effects of cocaine. [ABSTRACT FROM AUTHOR]