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Rationale: Chronic stress exposure disrupts the medial prefrontal cortex's (mPFC) ability to regulate impulses, leading to the loss of control over alcohol drinking in rodents, emphasizing the critical role of this forebrain area in regulating alcohol consumption. Moreover, chronic stress exposure causes lateralization of mPFC functions with volumetric and functional changes, resulting in hyperactivity in the right hemisphere and functional decrease in the left. Objectives: This study investigated the inhibitory role of the left prelimbic cortex (LPrL) on ethanol consumption induced by chronic social defeat stress (SDS) in male mice and to examine if inactivation of the LPrL causes disinhibition of the right mPFC, leading to an increase in ethanol consumption. We also investigated the role of lateralization and neurochemical alterations in the mPFC related to ethanol consumption induced by chronic SDS. To this end, we examined the activation patterns of ΔFosB, VGLUT2, and GAD67 in the left and right mPFC. Results: Temporarily blocking the LPrL or right PrL (RPrL) cortices during acute SDS did not affect male mice's voluntary ethanol consumption in male mice. When each cortex was blocked in mice previously exposed to chronic SDS, ethanol consumption also remained unaffected. However, male mice with LPrL lesions during chronic SDS showed an increase in voluntary ethanol consumption, which was associated with enhanced ΔFosB/VGLUT2-positive neurons within the RPrL cortex. Conclusions: The results suggest that the LPrL may play a role in inhibiting ethanol consumption induced by chronic SDS, while the RPrL may be involved in the disinhibition of ethanol consumption. [ABSTRACT FROM AUTHOR]

Background: Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. Methods: Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. Results: Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5′ regulatory region of the Aqp4 gene (−1096 bp to −1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. Conclusions: Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal.

Activity induced transcription factor ΔFosB plays a key role in different CNS disorders including epilepsy, Alzheimer's disease, and addiction. Recent findings suggest that ΔFosB drives cognitive deficits in epilepsy and together with the emergence of small molecule inhibitors of ΔFosB activity makes it an interesting therapeutic target. However, whether ΔFosB contributes to pathophysiology or provides protection in drug-resistant epilepsy is still unclear. In this study, ΔFosB was specifically downregulated by delivering AAV-shRNA into the hippocampus of chronically epileptic mice using the drug-resistant pilocarpine model of mesial temporal epilepsy (mTLE). Immunohistochemistry analyses showed that prolonged downregulation of ΔFosB led to exacerbation of neuroinflammatory markers of astrogliosis and microgliosis, loss of mossy fibers, and hippocampal granule cell dispersion. Furthermore, prolonged inhibition of ΔFosB using a 1JunD construct to block ΔFosB signaling in a mouse model of Alzheimer's disease, that exhibits spontaneous recurrent seizures, led to similar findings, with increased neuroinflammation and decreased NPY expression in mossy fibers. Together, these data suggest that seizure-induced ΔFosB, regardless of seizureetiology, is part of a homeostatic mechanism that protects the epileptic brain from further deterioration. [ABSTRACT FROM AUTHOR]

Activity induced transcription factor ΔFosB plays a key role in different CNS disorders including epilepsy, Alzheimer’s disease, and addiction. Recent findings suggest that ΔFosB drives cognitive deficits in epilepsy and together with the emergence of small molecule inhibitors of ΔFosB activity makes it an interesting therapeutic target. However, whether ΔFosB contributes to pathophysiology or provides protection in drug-resistant epilepsy is still unclear. In this study, ΔFosB was specifically downregulated by delivering AAV-shRNA into the hippocampus of chronically epileptic mice using the drug-resistant pilocarpine model of mesial temporal epilepsy (mTLE). Immunohistochemistry analyses showed that prolonged downregulation of ΔFosB led to exacerbation of neuroinflammatory markers of astrogliosis and microgliosis, loss of mossy fibers, and hippocampal granule cell dispersion. Furthermore, prolonged inhibition of ΔFosB using a ΔJunD construct to block ΔFosB signaling in a mouse model of Alzheimer’s disease, that exhibits spontaneous recurrent seizures, led to similar findings, with increased neuroinflammation and decreased NPY expression in mossy fibers. Together, these data suggest that seizure-induced ΔFosB, regardless of seizure-etiology, is part of a homeostatic mechanism that protects the epileptic brain from further deterioration.

Developmental morphine (MOR) exposure (DME) detrimentally affects the cognitive abilities of the next generation. It is shown that postnatal rearing environments and prenatal conditions effectively impact memory. The present study investigated the effects of DME, postweaning rearing, and sex on spatial learning and memory. At molecular level, we evaluated mRNA levels of brain‐derived neurotrophic factor, cyclic AMP response element‐binding protein (CREB), μ‐opioid receptor, and ΔFosB in the hippocampus of male offspring. Female Wistar rats were treated with escalating doses of MOR or saline before mating, gestation, and lactation. On Postnatal Day 22, the male and female pups were divided into 12 groups and raised for 2 months under different conditions: standard, isolated (ISO), or enriched environment. Afterward, the Morris water maze task measured spatial learning and reference memory; rats were then sacrificed to assess hippocampus gene expressions. Results indicated the DME and isolated rearing increased latency to find the hidden platform in male offspring. DME was insignificant in female offspring, whereas rearing environments significantly altered escape latency in both sexes. We also found that the enriched environment upregulated the brain‐derived neurotrophic factor mRNA in both saline and MOR groups, whereas it downregulated the mRNA levels of CREB1, μ‐opioid receptor, and ΔFosB in the MOR group. In addition, the DME enhanced CREB1, μ‐opioid receptor, and ΔFosB gene expression in the MOR + isolated group. Our findings signified the effects of DME, rearing environment, and sex on the spatial learning abilities of offspring. Also, we showed that DME and rearing conditions could manipulate hippocampal neurochemistry. [ABSTRACT FROM AUTHOR]

A growing body of evidence shows that cigarette smoking impairs cognitive performance. The 'Calcium Hypothesis' theory of neuronopathies reveals a critical role of aberrant calcium signaling in compromised cognitive functions. However, the underlying implications of abnormalities in calcium signaling in the neurotoxicity induced by cigarette smoke (CS) have not yet been identified. CACNA2D1, an important auxiliary subunit involved in the composition of voltage-gated calcium channels (VGCCs), was reported to affect the calcium signaling in neurons by facilitating VGCCs-mediated Ca2+ influx. ΔFOSB, an alternatively-spliced product of the Fosb gene, is an activity-dependent transcription factor induced robustly in the brain in response to environmental stimuli such as CS. Interestingly, our preliminary bioinformatics analysis revealed a significant co-expression between ΔFOSB and CACNA2D1 in brain tissues of patients with neurodegenerative diseases characterized by progressive cognitive decline. Therefore, we hypothesized that the activation of the ΔFOSB-CACNA2D1 axis in response to CS exposure might cause dysregulation of calcium homeostasis in hippocampal neurons via VGCCs-mediated Ca2+ influx, thereby contributing to cognitive deficits. To this end, the present study established a CS-induced mouse model of hippocampus-dependent cognitive impairment, in which the activation of the ΔFOSB-CACNA2D1 axis accompanied by severe calcium overload was observed in the mouse hippocampal tissues. More importantly, ΔFOSB knockdown-/overexpression-mediated inactivation/activation of the ΔFOSB-CACNA2D1 axis interdicted/mimicked CS-induced dysregulation of calcium homeostasis followed by severe cellular damage in HT22 mouse hippocampal neurons. Mechanistically speaking, a further ChIP-qPCR assay confirmed the physical interaction between transcription factor ΔFOSB and the Cacna2d1 gene promoter, suggesting a direct transcriptional regulation of the Cacna2d1 gene by ΔFOSB. Overall, our current work aims to deliver a unique insight into the neurotoxic mechanisms induced by CS to explore potential targets for intervention.

Sexual activity causes differential changes in the expression of markers of neural activation (c‐Fos and ΔFosB) and neural plasticity (Arc and BDNF/trkB), as determined either by Western Blot (BDNF, trkB, Arc, and ΔFosB) or immunohistochemistry (BDNF, trkB, Arc, and c‐Fos), in the hippocampus of male Roman high (RHA) and low avoidance (RLA) rats, two psychogenetically selected rat lines that display marked differences in sexual behavior (RHA rats exhibit higher sexual motivation and better copulatory performance than RLA rats). Both methods showed (with some differences) that sexual activity modifies the expression levels of these markers in the hippocampus of Roman rats depending on: (i) the level of sexual experience, that is, changes were usually more evident in sexually naïve than in experienced rats; (ii) the hippocampal partition, that is, BDNF and Arc increased in the dorsal but tended to decrease in the ventral hippocampus; (iii) the marker considered, that is, in sexually experienced animals BDNF, c‐Fos, and Arc levels were similar to those of controls, while ΔFosB levels increased; and (iv) the rat line, that is, changes were usually larger in RHA than RLA rats. These findings resemble those of early studies in RHA and RLA rats showing that sexual activity influences the expression of these markers in the nucleus accumbens, medial prefrontal cortex, and ventral tegmental area, and show for the first time that also in the hippocampus sexual activity induces neural activation and plasticity, events that occur mainly during the first phase of the acquisition of sexual experience and depend on the genotypic/phenotypic characteristics of the animals. [ABSTRACT FROM AUTHOR]

Treatment with levodopa (L-dopa) in Parkinson's disease (PD) leads to involuntary movements termed L-dopa-induced dyskinesia (LID). There are contradictory data about the influence of hormone therapy in female PD patients with LID and of 17-β-estradiol (E2) on animal correlates of LID-abnormal involuntary movements (AIMs). Our aim was to characterize the influence of E2 on motor impairment and AIMs in ovariectomized 6-hydroxydopamine (6-OHDA) rat model of PD. Half of the rats received empty and the other half implants filled with E2. Following the 6-OHDA surgery, the rats received daily treatment with either L-dopa or saline for 16 days. They were assessed for AIMs, contralateral rotations, and FAS. In the L-dopa-treated rats, E2 intensified and prolonged AIMs and contralateral rotations. On the other hand, it had no effect on motor impairment. Postmortem tyrosine hydroxylase immunostaining revealed an almost complete unilateral lesion of nigrostriatal dopaminergic neurons. E2 partially prevented the upregulation of striatal ΔFosB caused by dopamine depletion. L-dopa potentiated the upregulation of ΔFosB within the dopamine-depleted striatum and this effect was further enhanced by E2. We speculate that the potentiating effects of E2 on AIMs and on contralateral rotations could be explained by the molecular adaptations within the striatal medium spiny neurons of the direct and indirect striatofugal pathways. [ABSTRACT FROM AUTHOR]

In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD). We used both naturally occurring 7,8-DHF and the chemically modified form of DHF, the DHF-ME, to be used as a drug candidate for the treatment of PD and l -DOPA induced dyskinesia (LID), which is the debilitating side effect of l -DOPA therapy in PD. The ligand-protein interaction behavior for 7,8-DHF and 6,7-DHF-ME was found to be more effective with molecular docking and molecular stimulation studies of flavonoid compounds with TrkB receptor. Our study showed that 7,8-DHF delivered via intranasal route using a liposomal formulation ameliorated LID in hemiparkinsonian mice model when these mice were chronically administered with l -DOPA, which is the only current medication for relieving the clinical symptoms of PD. The present study also demonstrated that apart from reducing the LID, 7,8-DHF delivery directly to the brain via the intranasal route also corrected some long-term signaling adaptations involving ΔFosB and α Synuclein in the brain of dopamine (DA) depleted animals. [ABSTRACT FROM AUTHOR]

Parkinson's disease patients on chronic levodopa often suffer from motor complications, which tend to reduce their quality of life. Levodopa-induced dyskinesia (LID) is one of the most prevalent motor complications, often characterized by abnormal involuntary movements, and the pathogenesis of LID is still unclear but recent studies have suggested the involvement of autophagy. The onset of LID was mimicked by chronic levodopa treatment in a unilateral 6-hydroxydopamine (6-OHDA) -lesion rat model. Overexpression of ΔFosB in HEK293 cells to mimic the state of ΔFosB accumulation. The modulation of the AMP-activated protein kinase (AMPK)-mediated autophagy pathway using by metformin, AICAR (an AMPK activator), Compound C (an AMPK inhibitor) and chloroquine (an autophagy pathway inhibitor). The severity of LID was assessed by axial, limb, and orofacial (ALO) abnormal involuntary movements (AIMs) score and in vivo electrophysiology. The activity of AMPK pathway as well as autophagy markers and FosB-ΔFosB levels were detected by western blotting. RT-qPCR was performed to detect the transcription level of FosB-ΔFosB. The mechanism of autophagy dysfunction was further explored by immunofluorescence and transmission electron microscopy. In vivo experiments demonstrated that chronic levodopa treatment reduced AMPK phosphorylation, impaired autophagosome-lysosomal fusion and caused FosB-ΔFosB accumulation in the striatum of PD rats. Long-term metformin intervention improved ALO AIMs scores as well as reduced the mean power of high gamma (hγ) oscillations and the proportion of striatal projection neurons unstable in response to dopamine for LID rats. Moreover, the intervention of metformin promoted AMPK phosphorylation, ameliorated the impairment of autophagosome-lysosomal fusion, thus, promoting FosB-ΔFosB degradation to attenuate its accumulation in the striatum of LID rats. However, the aforementioned roles of metformin were reversed by Compound C and chloroquine. The results of in vitro studies demonstrated the ability of metformin and AICAR to attenuate ΔFosB levels by promoting its degradation, while Compound C and chloroquine could block this effect. In conclusion, our results suggest that long-term metformin treatment could promote ΔFosB degradation and thus attenuate the development of LID through activating the AMPK-mediated autophagy pathway. Overall, our results support the AMPK-mediated autophagy pathway as a novel therapeutic target for LID and also indicate that metformin is a promising therapeutic candidate for LID. • Autophagy dysfunction exists in the striatum of LID rats. • Metformin improves ALO AIMs scores and abnormal neuronal firing in LID rats. • Metformin ameliorates autophagy dysfunction in the striatum of LID rats. • Metformin attenuates ΔFosB accumulation by promoting ΔFosB degradation. [ABSTRACT FROM AUTHOR]

Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5′ regulatory region of the Aqp4 gene (−1096 bp to −1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal. [Display omitted] • Ketamine administration causes circulatory dysfunction of glymphatic system. • Ketamine administration induces cognitive impairment in mice. • Ketamine induces ΔFosb accumulation by increasing the expression of 5-HT2c receptor. • ΔFosb acts as a transcription factor to recognize and inhibit Aqp4 expression. [ABSTRACT FROM AUTHOR]

Environmental enrichment (EE) has been proven to reduce drug seeking and the development of addiction-related behaviors in rodent models, but the effects of EE on natural reward acquisition in the form of sweet beverages are poorly understood. Accumulating evidence shows that the intake of sugar, the main ingredient of sweet beverages, alters the dopaminergic system, leading to addiction-related physiological and molecular changes. Sugar in sweet beverages has been replaced with natural sweeteners, such as stevia extract, which has greater sweetener potential but no energy content. Our research group found that sucralose consumption increased the expression of ΔFosB in reward-related nuclei, suggesting activation of the dopaminergic system. The present study assessed the effects of EE on stevia consumption and the expression of ΔFosB in the nucleus accumbens, caudate putamen, and prefrontal cortex. Sixteen male Wistar rats, 21 days old, were randomly assigned to an EE group (n = 8) or standard environment (SE) group (n = 8) and reared for 30 days. On postnatal day 52 (PND52), the brains of four animals in each housing condition were extracted to determine basal ΔFosB levels. Stevia consumption with intermittent access and ΔFosB immunoreactivity were measured for 21 days in the remainder of the rats. Compared with SE animals, EE animals exhibited a reduction of stevia consumption and alterations of ΔFosB immunoreactivity in the reward system. These results indicate that EE reduces stevia consumption and the stevia-induced ΔFosB expression, suggesting addiction-related changes in dopaminergic nuclei, which may be interpreted as a neuroprotective effect. • Environmental enrichment decreases Stevia consumption in an intermittent access paradigm. • Stevia increases ΔFosB-ir in reward-related nuclei in animals that are housed under standard environment conditions. • Environmental enrichment prevents Stevia-induced ΔFosB accumulation in reward related nuclei. • Stevia intake leads activation of dopaminergic system like other natural rewards or drugs of abuse. [ABSTRACT FROM AUTHOR]

ΔFosB is a highly stable transcription factor that accumulates in specific brain regions upon chronic exposure to drugs of abuse, stress, or seizures, and mediates lasting behavioral responses. ΔFosB reportedly heterodimerizes with JunD forming a canonical bZIP leucine zipper coiled coil that clamps onto DNA. However, the striking accumulation of ΔFosB protein in brain upon chronic insult has brought its molecular status into question. Here, we demonstrate through a series of crystal structures that the ΔFosB bZIP domain self-assembles into stable oligomeric assemblies that defy the canonical arrangement. The ΔFosB bZIP domain also self-assembles in solution, and in neuron-like Neuro 2a cells it is trapped into molecular arrangements that are consistent with our structures. Our data suggest that, as ΔFosB accumulates in brain in response to chronic insult, it forms non-canonical assemblies. These species may be at the root of ΔFosB's striking protein stability, and its unique transcriptional and behavioral consequences.

Objective. Olanzapine (OLA), amisulpride (AMI), aripiprazole (ARI), and quetiapine (QUE) belong to antipsychotics, which administration represents still most reliable way for the treatment of schizophrenic and bipolar disorders. The intention of the present study was to explore whether the acute administration of a particular antipsychotic, indicated by the presence of c-Fos, will: a) stimulate neurons already activated by a long lasting homogeneous or heterogeneous stress preconditioning, indicated by the FosB/ΔFosB (ΔFosB) expression, or b) have a stimulatory effect only on a not activated, so called silent neurons. The pattern of ΔFosB and c-Fos spatial relationship was investigated in three forebrain structures, including the septal ventrolateral nucleus (seVL), the striatal dorsolateral area (stDL), and the shell of the nucleus accumbens (shell).

The onset and persistence of addiction phenotypes are, in part, mediated by transcriptional mechanisms in the brain that affect gene expression and, subsequently, neural circuitry. ΔFosB is a transcription factor that accumulates in the nucleus accumbens (NAc)—a brain region responsible for coordinating reward and motivation—after exposure to virtually every known rewarding substance, including cocaine and opioids. ΔFosB has also been shown to directly control gene transcription and behavior downstream of both cocaine and opioid exposure, but with potentially different roles in D1 and D2 medium spiny neurons (MSNs) in NAc. To clarify MSN subtype-specific roles for ΔFosB and investigate how these coordinate the actions of distinct classes of addictive drugs in NAc, we developed a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-based epigenome editing tool to induce endogenous ΔFosB expression in vivo in the absence of drug exposure. After inducing ΔFosB in D1- or D2-MSNs or both, we performed RNA sequencing on bulk male and female NAc tissue (n = 6–8/group). We found that ΔFosB induction elicits distinct transcriptional profiles in NAc by MSN subtype and by sex, establishing for the first time that ΔFosB mediates different transcriptional effects in males versus females. We also demonstrated that changes in D1-MSNs, but not those in D2-MSNs or both, significantly recapitulate changes in gene expression induced by cocaine self-administration. Together, these findings demonstrate the efficacy of a novel molecular tool for studying cell type–specific transcriptional mechanisms and shed new light on the activity of ΔFosB, a critical transcriptional regulator of drug addiction. [ABSTRACT FROM AUTHOR]

The rodent medial prefrontal cortex (mPFC) is anatomically divided into cingulate (Cg1), prelimbic (PrL), and infralimbic (IL) subareas. The left and right mPFC (L and RmPFC) process emotional responses induced by stress-related stimuli, and LmPFC and RmPFC inhibition elicit anxiogenesis and anxiolysis, respectively. Here we sought to investigate (i) the mPFC functional laterality on social avoidance/anxiogenic-like behaviors in male mice subjected to chronic social defeat stress (SDS), (ii) the effects of left prelimbic (PrL) inhibition (with local injection of CoCl2) on the RmPFC glutamatergic neuronal activation pattern (immunofluorescence assay), and (iii) the effects of the dorsal right mPFC (Cg1 + PrL) NMDA receptor blockade (with local injection of AP7) on the anxiety induced by left dorsal mPFC inhibition in mice exposed to the elevated plus maze (EPM). Results showed that chronic SDS induced anxiogenic-like behaviors followed by the rise of ΔFosB labeling and by ΔFosB + CaMKII double-labeling bilaterally in the Cg1 and IL subareas of the mPFC. Chronic SDS also increased ΔFosB and by ΔFosB + CaMKII labeling only on the right PrL. Also, the left PrL inhibition increased cFos + CaMKII labeling in the contralateral PrL and IL. Moreover, anxiogenesis induced by the left PrL inhibition was blocked by NMDA receptor antagonist AP7 injected into the right PrL. These findings suggest the lateralized control of the glutamatergic neurotransmission in the modulation of emotional-like responses in mice subjected to chronic SDS. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa ("kratom"), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa (“kratom”), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction.

The rodent medial prefrontal cortex (mPFC) is anatomically divided into cingulate (Cg1), prelimbic (PrL), and infralimbic (IL) subareas. The left and right mPFC (L and RmPFC) process emotional responses induced by stress-related stimuli, and LmPFC and RmPFC inhibition elicit anxiogenesis and anxiolysis, respectively. Here we sought to investigate (i) the mPFC functional laterality on social avoidance/anxiogenic-like behaviors in male mice subjected to chronic social defeat stress (SDS), (ii) the effects of left prelimbic (PrL) inhibition (with local injection of CoCl2) on the RmPFC glutamatergic neuronal activation pattern (immunofluorescence assay), and (iii) the effects of the dorsal right mPFC (Cg1 + PrL) NMDA receptor blockade (with local injection of AP7) on the anxiety induced by left dorsal mPFC inhibition in mice exposed to the elevated plus maze (EPM). Results showed that chronic SDS induced anxiogenic-like behaviors followed by the rise of ΔFosB labeling and by ΔFosB + CaMKII double-labeling bilaterally in the Cg1 and IL subareas of the mPFC. Chronic SDS also increased ΔFosB and by ΔFosB + CaMKII labeling only on the right PrL. Also, the left PrL inhibition increased cFos + CaMKII labeling in the contralateral PrL and IL. Moreover, anxiogenesis induced by the left PrL inhibition was blocked by NMDA receptor antagonist AP7 injected into the right PrL. These findings suggest the lateralized control of the glutamatergic neurotransmission in the modulation of emotional-like responses in mice subjected to chronic SDS.

Objectives: One factor contributing to the development of obesity is overeating palatable food. The palatability of food is driven by specific energy yielding combinations and flavor profiles that may contribute to its overconsumption. In rodents, restricted access to palatable food (PF) is a strong stimulus to trigger binge-type eating behavior (BTE), food anticipatory activity (FAA), effort behaviors and withdrawal symptoms. This is accompanied by plastic changes in corticolimbic areas associated with motivation and reward responses. Palatable food contains mainly a mixture of fat and sugar, thus, the contribution of each macronutrient for the behavioral and neuronal changes is unclear. Methods: In this study, Wistar rats were exposed to restricted access to 50% fat rich diet (FRD) or 50% sugar rich diet (SRD) in order to compare the intensity of BTE, FAA, effort behaviors and withdrawal responses. Results: In corticolimbic areas, c-Fos activation and ΔFosB accumulation were evaluated. After an acute exposition, rats ate more SRD than FRD, but FDR stimulated higher c-Fos. After chronic administration, the FDR group exhibited higher levels of BTE and FAA; this was associated with higher c-Fos and accumulation of ΔFosB in the corticolimbic system. Similar effects in the FRD group were observed after one week of withdrawal. Discussion: Present data indicate that the fat rich diet is a stronger stimulus than the sugar rich diet for the development of wanting behavior for reward and the underlying plastic changes in the corticolimbic system. The differential effects may be due to the differing caloric density of the diets. [ABSTRACT FROM AUTHOR]

• Maternal morphine exposure increase anxiety and morphine conditioning in offspring. • Social isolation rearing increase anxiety and morphine conditioning in offspring. • Enriched environment reduce anxiety and morphine conditioning in offspring. • Maternal morphine and social isolation enhance ΔFosB and μ- receptor proteins. • Enriched environment decline ΔFosB and μ-receptor proteins in reward pathway. Prenatal opioids exposure negatively affects the neurobehavioral abilities of children born from dependence dams. Adolescent housing conditions can buffer the detrimental impacts of early life experiences or contradictory can worsen individual psychosocial functions. The present study investigated the effects of maternal morphine dependence and different rearing conditions on behaviors and protein expression in brain reward circuits of male pups. Female Wistar rats a week before conception, during pregnancy and lactation were injected twice daily with escalating doses of morphine or saline. On a postnatal day 21, male pups were weaned and subjected to three different environments for two months: standard (STD), isolated (ISO), or enriched environment (EE). The anxiety and drug-related reward were measured using elevated plus maze, open field test, and conditioned place preference. Western blotting was used to determine the protein level of ΔFosB and μ-opioid receptor proteins in the striatum and the midbrain of male offspring, respectively. Results showed that maternal morphine administration dramatically increased anxiety-like and morphine place preference behaviors in offspring. Also, ISO condition aggravated these behavioral outcomes. While, rearing in EE could attenuate anxiety and morphine conditioning in pups. At molecular levels, maternal morphine exposure and social isolation markedly increased both of ΔFosB and μ-opioid receptor proteins expression. However, rearing in the EE declined ΔFosB protein expression. Together, these findings help to elucidate long lasting impacts of early life morphine exposure and rearing environment on the behavioral and molecular profile of addicted individuals. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications., Competing Interests: Authors report no competing of financial interest., (Copyright © 2024 Criscuolo et al.)

Activity of compound GSB-106, a low-molecular mimetic of loop 4 of the brain neurotrophic factor (BDNF), was studied in experimental morphine withdrawal syndrome simulated in outbred rats. Single and subchronic (5 intraperitoneal injections) administration of GSB-106 in a dose of 0.1 mg/kg significantly reduced the total index of morphine withdrawal syndrome by 55.2 and 45.6%, respectively. GSB-106 reduced the severity of some behavioral signs (piloerection, gnashing of teeth, wet-dog shaking, and runaway attempts), but had no effect on mechanical allodynia formed in the rats with dependence. Subchronic treatment with GSB-106 prevented the increase in the content of ΔFosB (product of early response gene) in the striatum induced by morphine withdrawal. The results confirmed the concept on the involvement of neurotrophins, specifically BDNF and its analogs, in the mechanisms associated with the formation of opiate dependence. [ABSTRACT FROM AUTHOR]

Repeated exposure to drugs produces a plethora of persistent brain changes, some of which underlie the development of drug addiction. An important objective of addiction research is to identify the brain changes that might mediate the transition from drug use to drug misuse. The persistent accumulation of the transcription factor, ∆FosB, following repeated drug exposure provides a means of achieving this objective. Experiments were conducted on sexually mature male Sprague-Dawley rats. The effects of extensive 3,4-methylenedioxymethamphetamine (MDMA) self-administration on immunohistochemical measurements of ∆FosB accumulation in 12 brain regions was compared with a matched, drug-naive, control group. Other groups were pretreated with MDMA (0.0 or 10.0 mg/kg, ip, once daily for 5 days), and the locomotor-activating effect of MDMA (200 μg/side) microinjected bilaterally into brain regions selected on the basis of the ∆FosB results was subsequently determined. MDMA self-administration significantly increased ∆FosB expression in the nucleus accumbens core, ventromedial and dorsomedial caudate-putamen, anterior cingulate, prelimbic, infralimbic, and orbitofrontal cortex, and both the central and basolateral amygdala, but not in the ventrolateral or dorsolateral caudate-putamen. Increases in the nucleus accumbens shell were substantial but were not significant following statistical correction for multiple comparisons. MDMA pretreatment enhanced MDMA-produced hyperactivity only when administered into the nucleus accumbens or the medial, but not the lateral, caudate-putamen, mirroring the ∆FosB results. These data compare favorably to results following repeated exposure to other drugs of abuse and support the idea of common neuroplastic changes following repeated drug exposure. [ABSTRACT FROM AUTHOR]

• Novel object memory impaired in the offspring of morphine-withdrawal parents. • Acetylation of histone H3 decreased in the PFC and hippocampus of the offspring. • ΔfosB decreased in the PFC and hippocampus of the offspring. It has been demonstrated that alteration in histone acetylation in the regions of the brain involved in the reward which may have an important role in morphine addiction. It is well established that epigenetic changes prior to birth influence the function and development of the brain. The current study was designed to evaluate changes in novel object memory, histone acetylation and ΔFosB in the brain of the offspring of morphine-withdrawn parents. Male and female Wistar rats received morphine orally for 21 following days. After ten days of abstinent, they were prepared for mating. The male offspring of the first parturition were euthanized on postnatal days 5, 21, 30 and 60. The novel object recognition (NOR) test was performed on adult male offspring. The amount of acetylated histone H3 and ΔFosB were evaluated in the prefrontal cortex (PFC) and hippocampus using western blotting. Obtained results indicated that the discrimination index in the NOR test was decreased in the offspring of morphine-withdrawn parents as compared with morphine-naïve offspring. In addition, the level of acetylated histone H3 was decreased in the PFC and hippocampus in the offspring of morphine-withdrawn parents during lifetime (postnatal days 5, 21, 30 and 60). In the case of ΔFosB, it also decreased in these regions in the morphine-withdrawn offspring. These results demonstrated that parental morphine exposure affects NOR memory, and decreased the level of histone H3 acetylation and ΔFosB in the PFC and hippocampus. Taken together, the effect of morphine might be transmitted to the next generation even after stop consuming morphine. [ABSTRACT FROM AUTHOR]

Shift-work and exposure to light at night lead to circadian disruption, which favors the use of alcohol and may be a risk factor for development of addictive behavior. This study evaluated in two experimental models of circadian disruption behavioral indicators of elevated alcohol intake and looked for ΔFosB, which is a transcription factor for neuronal plasticity in corticolimbic structures. Male Wistar rats were exposed to experimental shift-work (AR) or to constant light (LL) and were compared with a control group (LD). After 4 weeks in their corresponding conditions, control LD rats remained rhythmic, AR rats exhibited a loss of day-night patterns in the brain and the LL rats showed arrhythmicity in general activity and day-night PER1 patterns in corticolimbic structures. During 12 days of exposure to 10 percent alcohol solution, the AR group showed daily increased alcohol intake while LD and LL rats ingested similar amounts. After 72 h of alcohol deprivation, AR and LL rats increased alcohol intake in a binge-like test; this could be due not only to circadian disruption but also to stress and/or anxiety developed from the AR and LL manipulations. Associated to the increased alcohol intake, the AR and LL rats had significant accumulation of ΔFosB in the nucleus accumbens shell and decreased ΔFosB in the infralimbic cortex. Data here reported confirm that the disruption of temporal patterns favors the increased alcohol consumption and that this is associated with a differential accumulation of ΔFosB which may favor the development of addictive behavior. [ABSTRACT FROM AUTHOR]

• Each treatment helped improve the grasp dexterity in MCAO rats. • Each treatment helped improve the motor motivation in MCAO rats. • The dual treatment helped restore the balance of 5-HT level between bilateral NAc. • Each treatment could resume the expression of 5-HT 2C R in affected side of NAc. • The dual treatment could increase the expression of Δ FosB in affected side of NAc. The study aimed to explore the molecular mechanism of fluoxetine as an adjunct to therapeutic exercise to improve motor recovery using a rat cerebral ischemic model with middle cerebral artery occlusion (MCAO). We hypothesized that the nucleus accumbens (NAc) may be one of the responding areas to fluoxetine where relevant elevations in 5-hydroxytryptamine (5-HT) and ΔFosB were associated with motor behavioral recovery. Male Sprague-Dawley rats were randomly divided into five groups: rats without intervention; rats that underwent MCAO without exercise or fluoxetine; rats that underwent MCAO treated only with fluoxetine; rats that underwent MCAO treated only with exercise; and rats that underwent MCAO treated with both exercise and fluoxetine. Motor function and motivation were assessed by the fault footsteps test and the forced swimming test. 5-HT level in the bilateral NAc and the expression of 5-HT 2C receptor (5-HT 2C R) and ΔFosB in the ipsilesional (left) NAc were measured. Correlation was explored by Pearson correlation analysis. Our results indicated that either treatment helped improve the grasp dexterity of the affected limb, motor motivation, and resilience to adverse environment in MCAO rats. The dual treatment with fluoxetine and exercise may hasten the recovery process. The dual treatment helped restore the balance of 5-HT level between the bilateral NAc by significantly increasing its level in the ipsilesional side. Either treatment could resume the expression of 5-HT 2C R in the ipsilesional side of the NAc close to the normal level, which was correlated with motor recovery. The dual treatment significantly increased the expression of Δ FosB in the ipsilesional side of the NAc, which was correlated with the balance of 5-HT in the bilateral NAc, but not directly with motor recovery. In conclusion, the NAc may play an important role in driving physical motivation, which was possibly related to motor recovery after stroke. Fluoxetine may hasten the effectiveness of therapeutic exercise, possibly via regulating 5-HT and its receptors in the NAc. [ABSTRACT FROM AUTHOR]

Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug and the circumstances of consumption. However, drug-induced changes in gene expression underlying the saliency of these associations remain understudied. Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor ΔFosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate ΔFosB in hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. We investigated differences in mouse dorsal and ventral hippocampal ΔFosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of ΔFosB was subregion-specific, and that ΔFosB transcriptional activity in both the dorsal and ventral hippocampus is necessary for cocaine conditioned place preference. Further, we characterize changes in histone modifications at the FosB promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for FosB induction and multiple hippocampus-dependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal FosB gene promoter to cause ΔFosB induction critical for cocaine-related learning. [ABSTRACT FROM AUTHOR]

Long-term dopamine (DA) replacement therapy in Parkinson's disease (PD) leads to the development of abnormal involuntary movements known as L-Dopa-induced dyskinesia (LID). The transcription factor ΔFosB that is highly up-regulated in the striatum following chronic L-Dopa exposure may participate in the mechanisms of altered neuronal responses to DA generating LID. To identify intrinsic effects of elevated ΔFosB on L-Dopa responses, we induced transgenic ΔFosB overexpression in the striatum of parkinsonian nonhuman primates kept naïve of L-Dopa treatment. Elevated ΔFosB levels led to consistent appearance of LID since the initial acute L-Dopa tests. In line with this motor response, striatal projection neurons (SPNs) responded to DA with changes in firing frequency that reversed at the peak of the motor response, and these unstable SPN activity changes in response to DA are typically associated with the emergence of LID. Transgenic ΔFosB overexpression also induced up-regulation of other molecular markers of LID. These results support an autonomous role of striatal ΔFosB in the adaptive mechanisms altering motor responses to chronic DA replacement in PD. [ABSTRACT FROM AUTHOR]

Background: The substantial increase in use of 3,4-methylenedioxypyrovalerone (MDPV), a popular recreational synthetic cathinone, has raised legitimate questions about its behavioral consequences and abuse liability.Aims: The aim of this study was to study MDPV-induced neurobehavioral effects in the rat, using different paradigms traditionally developed to study drug-attributed addictive properties.Methods: Different patterns of intraperitoneal 3 mg/kg MDPV administration were investigated. Consequences on rat horizontal locomotion and behavior of acute, intermittent (once daily dosing over 10 days), and binge (three-time daily dosing for 3 days) MDPV administration as well as challenge after 10 day MDPV withdrawal were studied. The dopamine receptor-D1 antagonist, SCH23390, was bilaterally infused in the nucleus accumbens to determine the role of D1-receptors in MDPV-related effects on the associative memory recall using the conditioned place preference paradigm. In addition, in a separate experience using western blot, we investigated the effects of chronic MDPV administration (four injections during 24 h) on ΔFosB expression in the nucleus accumbens, caudate putamen, and prefrontal cortex.Results: Acute MDPV administration increased stereotypies and open arm entries in the elevated plus maze while SCH23390 abolished MDPV-induced enhancing effects on memory consolidation. Intermittent MDPV administration resulted in sensitization of MDPV-induced locomotor effects and tolerance during the following challenge. With binge MDPV administration, locomotor activity was not altered despite tolerance onset after challenge. SCH23390 abolished MDPV-induced conditioned place preference. Chronic MDPV administration induced ΔFosB accumulation in the nucleus accumbens, caudate putamen, and prefrontal cortex.Conclusions: Our findings clearly show that MDPV produces profound behavioral alterations mediated by the activation of the dopaminergic system similarly to other amphetamines. [ABSTRACT FROM AUTHOR]

Background: Besides the analgesic effect of tramadol, prolonged exposure to tramadol can induce adaptive changes thereby leading to dependence and tolerance. Tramadol induces its effect via µ-opioid receptor (MOR). However, tramadol has other targets such as serotonin and epinephrine transporters.Objective: CREB and ΔFosB are transcriptional factors, which are involved in the behavioral abnormalities underlying drug abuse. In this study, the effects of acute and chronic tramadol treatments on MOR, ΔFosB, and CREB levels were studied.Methods: For this purpose, 36 male Wistar rats were used. The animals were divided into two main groups. A total of 18 animals received tramadol (0, 5, and 10 mg/kg) acutely and 18 animals received the same doses for the following 14 days. One hour after the last injection, the NAC and PFC were dissected and kept at -80°C in liquid nitrogen. Using western blotting technique, the levels of MOR, ΔFosB, and p-CREB were evaluated.Results: In the NAC, acute tramadol exposure increases the levels of MOR and p-CREB. Moreover, chronic tramadol administration in this region results in elevated levels of MOR, ΔFosB and p-CREB compared with saline-treated rats. The levels of MOR and p-CREB in the PFC increased in both acute and chronic tramadol exposure. Also, ΔFosB levels increased only following chronic tramadol administration. The results revealed that adaptive changes occurred during drug exposure.Conclusion: We concluded that both CREB and ΔFosB played a role in tramadol dependence. Additionally, increased MOR levels during tramadol treatments might be due to receptor desensitization. [ABSTRACT FROM AUTHOR]

Abstract Background We previously reported that a single injection of ketamine prior to stress protects against the onset of depressive-like behavior and attenuates learned fear. However, the molecular pathways and brain circuits underlying ketamine-induced stress resilience are still largely unknown. Methods Here, we tested whether prophylactic ketamine administration altered neural activity in the prefrontal cortex and/or hippocampus. Mice were injected with saline or ketamine (30 mg/kg) 1 week before social defeat. Following behavioral tests assessing depressive-like behavior, mice were sacrificed and brains were processed to quantify ΔFosB expression. In a second set of experiments, mice were stereotaxically injected with viral vectors into ventral CA3 (vCA3) in order to silence or overexpress ΔFosB prior to prophylactic ketamine administration. In a third set of experiments, ArcCreERT2 mice, a line that allows for the indelible labeling of neural ensembles activated by a single experience, were used to quantify memory traces representing a contextual fear conditioning experience following prophylactic ketamine administration. Results Prophylactic ketamine administration increased ΔFosB expression in the ventral dentate gyrus and vCA3 of social defeat mice but not of control mice. Transcriptional silencing of ΔFosB activity in vCA3 inhibited prophylactic ketamine efficacy, while overexpression of ΔFosB mimicked and occluded ketamine's prophylactic effects. In ArcCreERT2 mice, ketamine administration altered memory traces representing the contextual fear conditioning experience in vCA3 but not in the ventral dentate gyrus. Conclusions Our data indicate that prophylactic ketamine may be protective against a stressor by altering neural activity, specifically the neural ensembles representing an individual stressor in vCA3. [ABSTRACT FROM AUTHOR]

Rosiglitazone induces adipogenesis in adipocyte and regulates cell survival and differentiation in number of cell types. However, whether PPARγ regulates the synthesis of milk fat and cell survival in goat mammary gland remains unknown. Rosiglitazone strongly enhanced cellular triacylglycerol content and accumulation of lipid droplet in goat mammary epithelial cells (GMEC). Furthermore, ΔFosB decreased the expression of PPARγ at both mRNA and protein levels, and rosiglitazone‐induced milk fat synthesis was abolished by ΔFosB overexpression. ΔFosB reduced milk fat synthesis and enhanced saturated fatty acid concentration. Rosiglitazone increased the number of GMEC in G0/G1 phase and inhibited cell proliferation, and these effects were improved by overexpression of ΔFosB. ΔFosB was found to promote the expression of Bcl‐2 and suppress the expression of Bax, and protected GMEC from apoptosis induced by rosiglitazone. Intracellular calcium trafficking assay revealed that rosiglitazone markedly increased intracellular calcium concentration. ΔFosB protected GMEC from apoptosis induced by intracellular Ca2+ overload. ΔFosB increased MMP‐9 gelatinolytic activity. SB‐3CT, an MMP‐9 inhibitor, suppressed the expression of Bcl‐2, and increased intracellular calcium levels, and this effect was abolished by ΔFosB overexpression. SB‐3CT induced GMEC apoptosis and this effect was inhibited by ΔFosB overexpression. These findings suggest that ΔFosB regulates rosiglitazone‐induced milk fat synthesis and cell survival. Therefore, ΔFosB may be an important checkpoint to control milk fat synthesis and cell apoptosis. ΔFosB suppresses PPARγ agonist rosiglitazone‐induced cellular lipid‐droplets accumulation and protects cells from PPARγ activated‐induced apoptosis. ΔFosB also increased MMP‐9 gelatinolytic activity, and inhibition of MMP‐9 suppressed the expression of Bcl‐2 and increased intracellular calcium levels, and these effects were improved by overexpression of ΔFosB. [ABSTRACT FROM AUTHOR]

Group II metabotropic glutamate receptors (mGlu 2/3 receptors) have been regarded as promising candidates for the treatment of L-DOPA-induced dyskinesia (LID); however, confirmation is still lacking. As the hub of the basal ganglia circuit, the striatum plays a critical role in action control. Supersensitive responsiveness of glutamatergic corticostriatal input may be the key mechanism for the development of LID. In this study, we first examined the potency of LY354740 (12 mg/kg, i.p.) in modulating glutamate and dopamine release in lesioned striatum of stable LID rats. Then, we injected LY354740 (20nmoL or 40nmoL in 4 μL of sterile 0.9 % saline) directly into the lesioned striatum to verify its ability to reduce or attenuate L-DOPA-induced abnormal involuntary movements. In experiment conducted in established LID rats, after continuous injection for 4 days, we found that LY354740 significantly reduced the expression of dyskinesia. In another experiment conducted in parkinsonism rat models, we found that LY354740 attenuated the development of LID with an inverted-U dose–response curve. The role of LY354740 in modulating striatal expressions of LID-related molecular changes was also assessed after these behavioral experiments. We found that LY354740 significantly inhibited abnormal expressions of p-Fyn/p-NMDA/p-ERK1/2/p-HistoneH3/ΔFosB, which is in line with its ability to alleviate abnormal involuntary movements in both LID expression and induction phase. Our study indicates that activation of striatal mGlu 2/3 receptors can attenuate the development of dyskinesia in parkinsonism rats and provide some functional improvements in LID rats by inhibiting LID-related molecular changes. • Activation of striatal mGluR2/3 can reduce the expression of dyskinesia. • Activation of striatal mGluR2/3 can attenuate the development of dyskinesia. • mGluR2/3 agonist can inhibit LID-associated molecular alterations. [ABSTRACT FROM AUTHOR]

Methamphetamine abuse co-occurring with HIV infection presents neuropathology in brain regions that mediate reward and motivation. A neuronal signaling cascade altered acutely by meth and some HIV-1 proteins is the mitogen-activated protein kinase (MAPK) pathway. It remains unknown if chronic co-exposure to meth and HIV-1 proteins converge on MAPK in vivo. To make this determination, we studied young adult Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats that self-administered meth (0.02-0.04 mg/kg/0.05 ml iv infusion, 2 h/day for 21 days) and their saline-yoked controls. One day following the operant task, rats were killed. Brain regions involved in reward-motivation [i.e., nucleus accumbens (NA) and ventral pallidum (VP)], were assayed for a MAPK cascade protein, extracellular signal-regulated kinase (ERK), and a downstream transcription factor, ΔFosB. In the NA, activated (phosphorylated; p) ERK-to-ERK ratio (pERK/ERK) was increased in meth-exposed Tg rats versus saline Tg controls, and versus meth non-Tg rats. ΔFosB was increased in meth Tg rats versus saline and meth non-Tg rats. Assessment of two targets of ΔFosB-regulated transcription revealed (1) increased dopamine D1 receptor (D1R) immunoreactivity in the NA shell of Tg-meth rats versus saline Tg controls, but (2) no changes in the AMPA receptor subunit, GluA2. No changes related to genotype or meth occurred for ERK, ΔFosB or D1R protein in the VP. Results reveal a region-specific activation of ERK, and increases in ΔFosB and D1R expression induced by HIV-1 proteins and meth. Such effects may contribute to the neuronal and behavioral pathology associated with meth/HIV comorbidity. [ABSTRACT FROM AUTHOR]

A growing number of studies implicate the brain's reward circuitry in aggressive behavior. However, the cellular and molecular mechanisms within brain reward regions that modulate the intensity of aggression as well as motivation for it have been underexplored. Here, we investigate the cell-type-specific influence of ΔFosB, a transcription factor known to regulate a range of reward and motivated behaviors, acting in the nucleus accumbens (NAc), a key reward region, in male aggression in mice. We show that ΔFosB is specifically increased in dopamine D1 receptor (Drd1)-expressing medium spiny neurons (D1-MSNs) in NAc after repeated aggressive encounters. Viral-mediated induction of ΔFosB selectively in D1-MSNs of NAc intensifies aggressive behavior without affecting the preference for the aggression-paired context in a conditioned place preference (CPP) assay. In contrast, ΔFosB induction selectively in D2-MSNs reduces the time spent exploring the aggression-paired context during CPP without affecting the intensity of aggression per se. These data strongly support a dissociable cell-type-specific role for ΔFosB in the NAc in modulating aggression and aggression reward. [ABSTRACT FROM AUTHOR]

ΔFosB is a member of the activator protein-1 family of transcription factors. ΔFosB has low constitutive expression in the central nervous system and is induced after exposure of rodents to intermittent hypoxia (IH), a model of the arterial hypoxemia that accompanies sleep apnea. We hypothesized ΔFosB in the nucleus of the solitary tract (NTS) contributes to increased mean arterial pressure (MAP) during IH. The NTS of 11 male Sprague-Dawley rats was injected (3 sites, 100 nl/site) with a dominant negative construct against ΔFosB (ΔJunD) in an adenoassociated viral vector (AAV)-green fluorescent protein (GFP) reporter. The NTS of 10 rats was injected with AAV-GFP as sham controls. Two weeks after NTS injections, rats were exposed to IH for 8 h/day for 7 days, and MAP was recorded using telemetry. In the sham group, 7 days of IH increased MAP from 99.8 ± 1.1 to 107.3 ± 0.5 mmHg in the day and from 104.4 ± 1.1 to 109.8 ± 0.6 mmHg in the night. In the group that received ΔJunD, IH increased MAP during the day from 95.9 ± 1.7 to 101.3 ± 0.4 mmHg and from 100.9 ± 1.7 to 102.8 ± 0.5 mmHg during the night (both IH-induced changes in MAP were significantly lower than sham, P < 0.05). After injection of the dominant negative construct in the NTS, IH-induced ΔFosB immunoreactivity was decreased in the paraventricular nucleus (P < 0.05); however, no change was observed in the rostral ventrolateral medulla. These data indicate that ΔFosB within the NTS contributes to the increase in MAP induced by IH exposure. [ABSTRACT FROM AUTHOR]

Chronic social defeat has been found to be stressful and to affect many aspects of the brain and behaviors in males. However, relatively little is known about its effects on females. In the present study, we examined the effects of repeated social defeat on social approach and anxiety-like behaviors as well as the neuronal activation in the brain of sexually naïve female Mongolian gerbils (Meriones unguiculatus). Our data indicate that repeated social defeats for 20 days reduced social approach and social investigation, but increased risk assessment or vigilance to an unfamiliar conspecific. Such social defeat experience also increased anxiety-like behavior and reduced locomotor activity. Using ΔFosB-immunoreactive (ΔFosB-ir) staining as a marker of neuronal activation in the brain, we found significant elevations by social defeat experience in the density of ΔFosB-ir stained neurons in several brain regions, including the prelimbic (PL) and infralimbic (IL) subnuclei of the prefrontal cortex (PFC), CA1 subfields (CA1) of the hippocampus, central subnuclei of the amygdala (CeA), the paraventricular nucleus (PVN), dorsomedial nucleus (DMH), and ventrolateral subdivision of the ventromedial nucleus (VMHvl) of the hypothalamus. As these brain regions have been implicated in social behaviors and stress responses, our data suggest that the specific patterns of neuronal activation in the brain may relate to the altered social and anxiety-like behaviors following chronic social defeat in female Mongolian gerbils. • Chronic social defeat induced social anxiety including social fear and social avoidance. • Chronic social defeat also increased anxiety-like behaviors. • Chronic social defeat altered the density of ΔFosB-ir neurons in a brain region-specific manner. • Altered ΔFosB density in the PVN, DMH, VMHvl, and hippocampus correlated with social fear and avoidance. • Altered ΔFosB density in the PVN, DMH, PIR, and SON correlated with anxiety-like behavior. [ABSTRACT FROM AUTHOR]

A growing body of evidence shows that cigarette smoking impairs cognitive performance. The ' Calcium Hypothesis ' theory of neuronopathies reveals a critical role of aberrant calcium signaling in compromised cognitive functions. However, the underlying implications of abnormalities in calcium signaling in the neurotoxicity induced by cigarette smoke (CS) have not yet been identified. CACNA2D1, an important auxiliary subunit involved in the composition of voltage-gated calcium channels (VGCCs), was reported to affect the calcium signaling in neurons by facilitating VGCCs-mediated Ca2+ influx. ΔFOSB, an alternatively-spliced product of the Fosb gene, is an activity-dependent transcription factor induced robustly in the brain in response to environmental stimuli such as CS. Interestingly, our preliminary bioinformatics analysis revealed a significant co-expression between ΔFOSB and CACNA2D1 in brain tissues of patients with neurodegenerative diseases characterized by progressive cognitive decline. Therefore, we hypothesized that the activation of the ΔFOSB-CACNA2D1 axis in response to CS exposure might cause dysregulation of calcium homeostasis in hippocampal neurons via VGCCs-mediated Ca2+ influx, thereby contributing to cognitive deficits. To this end, the present study established a CS-induced mouse model of hippocampus-dependent cognitive impairment, in which the activation of the ΔFOSB-CACNA2D1 axis accompanied by severe calcium overload was observed in the mouse hippocampal tissues. More importantly, ΔFOSB knockdown-/overexpression-mediated inactivation/activation of the ΔFOSB-CACNA2D1 axis interdicted/mimicked CS-induced dysregulation of calcium homeostasis followed by severe cellular damage in HT22 mouse hippocampal neurons. Mechanistically speaking, a further ChIP-qPCR assay confirmed the physical interaction between transcription factor ΔFOSB and the Cacna2d1 gene promoter, suggesting a direct transcriptional regulation of the Cacna2d1 gene by ΔFOSB. Overall, our current work aims to deliver a unique insight into the neurotoxic mechanisms induced by CS to explore potential targets for intervention. [Display omitted] • Cigarette smoke (CS) exposure impaired cognitive performance in mice. • CS exposure induced adverse neuropathological changes in the mouse hippocampus. • CS exposure triggered calcium (Ca2+) overload in the mouse hippocampus. • ΔFOSB-CACNA2D1 axis mediated CS-induced Ca2+ overload in hippocampal neurons. • ΔFOSB transcriptionally activated the Cacna2d1 gene by directly binding to its promoter. [ABSTRACT FROM AUTHOR]

Volatile anesthetics elicit neurodevelopmental toxicity in rodents and primates and lead to more exaggerated anxiety-like behavior in response to future stress. Anxiety and fear are closely correlated and maladaptive fear-associated learning is regarded as the core mechanism underlying anxiety-related disorders. However, little is known about the interaction between early-life anesthetic exposure and future stress and the accompanying effect on fear-associated learning. In the present study, we evaluated the alterations in fear-associated learning (fear acquisition and extinction) occurring in mice receiving repeated neonatal isoflurane exposure and chronic variable stress (CVS) successively through a series of fear conditioning, fear reinforcing, and fear extinction paradigms. The corticosterone (CORT) response during CVS and the immunohistochemical levels of ΔFosB and c-Fos expression in the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG) after the extinction retrieval test were also investigated. The results showed that neonatal isoflurane exposure could increase CORT levels following the first diurnal CVS procedure, but not after completion of the whole CVS paradigm. Neonatal isoflurane exposure exerted a repressive effect on fear acquisition, in contrast to that seen with CVS. Neonatal isoflurane exposure and CVS both exerted suppressive effects on fear extinction and there was a significant synergy between them. Furthermore, neonatal isoflurane exposure facilitated CVS-mediated ΔFosB accumulation in the BLA and the hippocampal DG, which may have been responsible for c-Fos expression deficits and fear extinction impairment. Collectively, these findings contribute to the understanding of the interaction between early-life anesthetic exposure and future stress, as well as the accompanying behavioral alterations. • Early-life anesthetic exposure can elicit potential neurodevelopmental toxicity. • Neonatal isoflurane exposure increases brain's susceptibility to stress in mice. • Neonatal isoflurane exposure facilitates stress-related fear extinction deficit. • Neonatal isoflurane exposure promotes ΔFosB accumulation following CVS. • ΔFosB accumulation in BLA and DG is correlated with fear extinction deficit. [ABSTRACT FROM AUTHOR]

L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received daily L-DOPA treatment for 3 weeks, and abnormal involuntary movements (AIMs) were assessed every other day. PD98059 was injected in the lateral ventricle daily for 12 days starting from day 10 of L-DOPA treatment. Striatal molecular markers of LID were analyzed together with gene regulation using microarray. The administration of PD98059 significantly reduced AIMs. In addition, ERK activation and other associated molecular changes including ΔFosB were reversed in rats treated with the MEK inhibitor. PD98059 induced significant up-regulation of 418 transcripts and down-regulation of 378 transcripts in the striatum. Tyrosine hydroxylase (Th) and aryl hydrocarbon receptor nuclear translocator (Arnt) genes were down-regulated in lesioned animals and up-regulated in L-DOPA-treated animals. Analysis of protein levels showed that PD98059 reduced the striatal TH. These results support the association of p-ERK1/2, ΔFosB, p-H3 to the regulation of TH and ARNT in the mechanisms of LID, and pinpoint other gene regulatory changes, thus providing clues for identifying new targets for LID therapy.

Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction. [ABSTRACT FROM AUTHOR]

Approximately 50% of depressed individuals fail to achieve remission with first-line antidepressant drugs and a third remain treatment-resistant. When first-line antidepressant treatment is unsuccessful, second-line strategies include dose optimisation, switching to another antidepressant, combination with another antidepressant, or augmentation with a non-antidepressant medication. Much of the evidence for the efficacy of augmentation strategies comes from studies using lithium to augment the effects of tricyclic antidepressants. The neural circuitry underlying the therapeutic effects of lithium augmentation is not yet fully understood. Recently, we reported that chronic treatment with a combination of lithium and the antidepressant desipramine, exerted antidepressant-like behavioural effects in a mouse strain (BALB/cOLaHsd) that did not exhibit an antidepressant-like behavioural response to either drug alone. In the present study, we used this model in combination with ΔFosB/FosB immunohistochemistry to identify brain regions chronically affected by lithium augmentation of desipramine when compared to either treatment alone. The data suggest that the dorsal raphe nucleus and the CA3 regions of the dorsal hippocampus are key nodes in the neural circuitry underlying antidepressant action of lithium augmentation of desipramine. These data give new insight into the neurobiology underlying the mechanism of lithium augmentation in the context of treatment-resistant depression. [ABSTRACT FROM AUTHOR]

Early-onset ethanol consumption predicts later development of alcohol use disorders. Age-related differences in reactivity to ethanol's effects may underlie this effect. Adolescent rats are more sensitive and less sensitive than adults to the appetitive and aversive behavioral effects of ethanol, respectively, and more sensitive to the neurotoxic effects of experimenter-administered binge doses of ethanol. However, less is known about age-related differences in the neural consequences of self-administered ethanol. ΔFosB is a transcription factor that accumulates after chronic drug exposure and serves as a molecular marker of neural plasticity associated with the transition to addiction. We analyzed the impact of chronic (18 two-bottle choice intake sessions spread across 42 days, session length: 18 h) ethanol [or only vehicle (control group)] self-administration during adolescence or adulthood on the induction of ΔFosB in several brain areas, anxiety-like behavior, and ethanol-induced locomotor activity and conditioned place preference (CPP) in Wistar rats. Adolescent rats exhibited a progressive escalation of ethanol intake and preference, whereas adult rats exhibited a stable pattern of ingestion. Few behavioral differences in the open field or light-dark test were observed after the intake test. Furthermore, ethanol self-administration did not promote the expression of ethanol-induced CPP. There were, however, large age-related differences in the neural consequences of ethanol drinking: a significantly greater number of ethanol-induced ΔFosB-positive cells was found in adolescents vs. adults in the prelimbic cortex, dorsolateral striatum, nucleus accumbens core and shell, and central amygdala nucleus capsular and basolateral amygdala, with sex-related differences found at central amygdala. This greater ethanol-induced ΔFosB induction may represent yet another age-related difference in the sensitivity to ethanol that may put adolescents at higher risk for problematic ethanol use. [ABSTRACT FROM AUTHOR]

Physical exercise can improve brain function, but the effects of exercise cessation are largely unknown. This study examined the time-course profile of hippocampal neurogenesis following exercise cessation. Male C57BL/6 mice were randomly assigned to either a control (Con) or an exercise cessation (ExC) group. Mice in the ExC group were reared in a cage with a running wheel for 8 wk and subsequently placed in a standard cage to cease the exercise. Exercise resulted in a significant increase in the density of doublecortin (DCX)-positive immature neurons in the dentate gyrus (at week 0). Following exercise cessation, the density of DCX-positive neurons gradually decreased and was significantly lower than that in the Con group at 5 and 8 wk after cessation, indicating that exercise cessation leads to a negative rebound in hippocampal neurogenesis. Immunohistochemistry analysis suggests that the negative rebound in neurogenesis is caused by diminished cell survival, not by suppression of cell proliferation and neural maturation. Neither elevated expression of ΔFosB, a transcription factor involved in neurogenesis regulation, nor increased plasma corticosterone, were involved in the negative neurogenesis rebound. Importantly, exercise cessation suppressed ambulatory activity, and a significant correlation between change in activity and DCX-positive neuron density suggested that the decrease in activity is involved in neurogenesis impairment. Forced treadmill running following exercise cessation failed to prevent the negative neurogenesis rebound. This study indicates that cessation of exercise or a decrease in physical activity is associated with an increased risk for impaired hippocampal function, which might increase vulnerability to stress-induced mood disorders. [ABSTRACT FROM AUTHOR]