Effects of cocaine base paste on anxiety-like behavior and immediate-early gene expression in nucleus accumbens and medial prefrontal cortex of female mice.

RATIONALE: Cocaine base paste (CBP) is an illegal drug of abuse usually consumed by adolescents in a socio-economically vulnerable situation. Repeated drug use targets key brain circuits disrupting the processes that underlie emotions and cognition. At the basis of such neuroadaptations lie changes in the expression of immediate-early genes (IEGs). Nevertheless, changes in transcriptional regulation associated with CBP consumption remain unknown. OBJECTIVES: We aimed to describe behavioral phenotype related to locomotion, anxiety-like behavior, and memory of CBP-injected mice and to study IEGs expression after an abstinence period. METHODS: Five-week-old female CF-1 mice were i.p. injected daily with vehicle or CBP (40 mg/kg) for 10 days and subjected to a 10-day period of abstinence. Open field and novel object recognition tests were used to evaluate locomotion and anxiety-like behaviors and recognition memory, respectively, during chronic administration and after abstinence. After abstinence, prefrontal cortex (mPFC) and nucleus accumbens (NAc) were isolated and gene expression analysis performed through real-time PCR. RESULTS: We found an increase in locomotion and anxiety-like behavior during CBP administration and after the abstinence period. Furthermore, the CBP group showed impaired recognition memory after abstinence. Egr1, FosB, ΔFosB, Arc, Bdnf, and TrkB expression was upregulated in CBP-injected mice in NAc and FosB, ΔFosB, Arc, and Npas4 expression was downregulated in mPFC. We generated an anxiety score and found positive and negative correlations with IEGs expression in NAc and mPFC, respectively. CONCLUSION: Our results suggest that chronic CBP exposure induced alterations in anxiety-like behavior and recognition memory. These changes were accompanied by altered IEGs expression.

Expression of immediate early genes in brain reward circuitries: Differential regulation by psychostimulant and opioid drugs.

Although some of the clinical manifestations of substance use disorders might be superficially similar, it is highly likely that different classes of abused drugs including opioids (heroin, morphine, and oxycodone, other opioids) and psychostimulants (cocaine and amphetamines) cause different neuroadaptations in various brain regions dependent in the distribution and concentration of their biochemical sites of actions. In fact, different molecular networks are indeed impacted by acute and chronic administration of addictive substances. Some of the genes whose expression is influenced by the administration of these substances are immediate-early genes (IEGs). IEGs include classes of low expression genes that can become very highly induced within seconds or minutes of activation by endogenous or exogenous stimuli. These IEGs might play important roles in activating target genes that regulate adaptations implicated in the behavioral manifestations diagnosed as addiction. Therefore, the purpose of this review is to provide an overview of recent data on the effects of psychostimulants and opioids on IEG expression in the brain. The review documents some contrasting effects of these classes of drugs on gene expression and indicates that further studies are necessary to identify the specific effects of each drug class when trying to predict clinical responses to therapeutic agents.

Environmental enrichment protects against stress-induced anxiety: Role of glucocorticoid receptor, ERK, and CREB signaling in the basolateral amygdala.

Environmental enrichment (EE) is an experimental animal model that enhances an animal's opportunity to interact with sensory, motor, and social stimuli, compared to standard laboratory conditions. A prominent benefit of EE is the reduction of stress-induced anxiety. The relationship between stress and the onset of anxiety-like behavior has been widely investigated in experimental research, showing a clear correlation with structural changes in the hippocampus and basolateral amygdala (BLA). However, the mechanisms by which EE exerts its protective roles in stress and anxiety remain unclear, and it is not known whether EE reduces the effects of acute stress on animal behavior shortly following the cessation of stress. We found that EE can prevent the emergence of anxiety-like symptoms in rats measured immediately after acute restraint stress (1 h) and this effect is not due to changes in systemic release of corticosterone. Rather, we found that stress promotes a rapid increase in the nuclear translocation of glucocorticoid receptor (GR) in the BLA, an effect prevented by previous EE exposure. Furthermore, we observed a reduction of ERK (a MAPK protein) and CREB activity in the BLA promoted by both EE and acute stress. Finally, we found that EE decreases the expression of the immediate-early gene EGR-1 in the BLA, indicating a possible reduction of neuronal activity in this region. Hyperactivity of BLA neurons has been reported to accompany anxiety-like behavior and changes in this process may be one of the mechanism by which EE exerts its protective effects against stress-induced anxiety.

Sleep deprivation and gene expression.

Sleep occurs in a wide range of animal species as a vital process for the maintenance of homeostasis, metabolic restoration, physiological regulation, and adaptive cognitive functions in the central nervous system. Long-term perturbations induced by the lack of sleep are mostly mediated by changes at the level of transcription and translation. This chapter reviews studies in humans, rodents, and flies to address the various ways by which sleep deprivation affects gene expression in the nervous system, with a focus on genes related to neuronal plasticity, brain function, and cognition. However, the effects of sleep deprivation on gene expression and the functional consequences of sleep loss are clearly not restricted to the cognitive domain but may include increased inflammation, expression of stress-related genes, general impairment of protein translation, metabolic imbalance, and thermal deregulation.

Comprehensive analysis of tissue preservation and recording quality from chronic multielectrode implants.

Multielectrodes have been used with great success to simultaneously record the activity of neuronal populations in awake, behaving animals. In particular, there is great promise in the use of this technique to allow the control of neuroprosthetic devices by human patients. However, it is crucial to fully characterize the tissue response to the chronic implants in animal models ahead of the initiation of human clinical trials. Here we evaluated the effects of unilateral multielectrode implants on the motor cortex of rats weekly recorded for 1-6 months using several histological methods to assess metabolic markers, inflammatory response, immediate-early gene (IEG) expression, cytoskeletal integrity and apoptotic profiles. We also investigated the correlations between each of these features and firing rates, to estimate the impact of post-implant time on neuronal recordings. Overall, limited neuronal loss and glial activation were observed on the implanted sites. Reactivity to enzymatic metabolic markers and IEG expression were not significantly different between implanted and non-implanted hemispheres. Multielectrode recordings remained viable for up to 6 months after implantation, and firing rates correlated well to the histochemical and immunohistochemical markers. Altogether, our results indicate that chronic tungsten multielectrode implants do not substantially alter the histological and functional integrity of target sites in the cerebral cortex.

Induction of Zenk protein expression within the nucleus taeniae of the amygdala of pigeons following tone and shock stimulation

In this study, we evaluated the expression of the Zenk protein within the nucleus taeniae of the pigeon’s amygdala (TnA) after training in a classical aversive conditioning, in order to improve our understanding of its functional role in birds. Thirty-two 18-month-old adult male pigeons (Columba livia), weighing on average 350 g, were trained under different conditions: with tone-shock associations (experimental group; EG); with shock-alone presentations (shock group; SG); with tone-alone presentations (tone group; TG); with exposure to the training chamber without stimulation (context group; CG), and with daily handling (naive group; NG). The number of immunoreactive nuclei was counted in the whole TnA region and is reported as density of Zenk-positive nuclei. This density of Zenk-positive cells in the TnA was significantly greater for the EG, SG and TG than for the CG and NG (P < 0.05). The data indicate an expression of Zenk in the TnA that was driven by experience, supporting the role of this brain area as a critical element for neural processing of aversive stimuli as well as meaningful novel stimuli.

Induction of Zenk protein expression within the nucleus taeniae of the amygdala of pigeons following tone and shock stimulation.

In this study, we evaluated the expression of the Zenk protein within the nucleus taeniae of the pigeon's amygdala (TnA) after training in a classical aversive conditioning, in order to improve our understanding of its functional role in birds. Thirty-two 18-month-old adult male pigeons (Columba livia), weighing on average 350 g, were trained under different conditions: with tone-shock associations (experimental group; EG); with shock-alone presentations (shock group; SG); with tone-alone presentations (tone group; TG); with exposure to the training chamber without stimulation (context group; CG), and with daily handling (naive group; NG). The number of immunoreactive nuclei was counted in the whole TnA region and is reported as density of Zenk-positive nuclei. This density of Zenk-positive cells in the TnA was significantly greater for the EG, SG and TG than for the CG and NG (P < 0.05). The data indicate an expression of Zenk in the TnA that was driven by experience, supporting the role of this brain area as a critical element for neural processing of aversive stimuli as well as meaningful novel stimuli.

Neurodegeneration and prolonged immediate early gene expression throughout cortical areas of the rat brain following acute administration of dizocilpine.

N-methyl-d-aspartate receptor antagonist drugs (NMDA-A), such as dizocilpine (MK801), induce long-lasting behavioral disturbances reminiscent to psychotic disorders in humans. To identify cortical structures affected by NMDA-A, we used a single dose of MK801 (10 mg/kg) that caused low and high neurodegeneration in intact and orchiectomized male rats, respectively. Degenerating somas (neuronal death) and axonal/synaptic endings (terminal degeneration) were depicted by a silver technique, and functionally affected cortical neuronal subpopulations by Egr-1, c-Fos, and FosB/DeltaFosB-immunolabeling. In intact males, MK801 triggered a c-Fos induction that remained high for more than 24 h in selected layers of the retrosplenial, somatosensory and entorhinal cortices. MK801-induced neurodegeneration reached its peak at 72 h. Degenerating somas were restricted to layer IV of the granular subdivision of the retrosplenial cortex, and were accompanied by suppression of Egr-1 immunolabeling. Terminal degeneration extended to selected layers of the retrosplenial, somatosensory and parahippocampal cortices, which are target areas of retrosplenial cortex. Induction of FosB/DeltaFosB by MK801 also extended to the same cortical layers affected by terminal degeneration, likely reflecting the damage of synaptic connectivity. In orchiectomized males, the neurodegenerative and functional effects of MK801 were exacerbated. Degenerative somas in layer IV of the retrosplenial cortex significantly increased, with a parallel enhancement of terminal degeneration and FosB/DeltaFosB-expression in the mentioned cortical structures, but no additional areas were affected. These observations reveal that synaptic dysfunction/degeneration in the retrosplenial, somatosensory and parahippocampal cortices might underlie the long-lasting impairments induced by NMDA-A.

Water deprivation-induced sodium appetite: humoral and cardiovascular mediators and immediate early genes.

Adult rats deprived of water for 24-30 h were allowed to rehydrate by ingesting only water for 1-2 h. Rats were then given access to both water and 1.8% NaCl. This procedure induced a sodium appetite defined by the operational criteria of a significant increase in 1.8% NaCl intake (3.8 +/- 0.8 ml/2 h; n = 6). Expression of Fos (as assessed by immunohistochemistry) was increased in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), subfornical organ (SFO), and supraoptic nucleus (SON) after water deprivation. After rehydration with water but before consumption of 1.8% NaCl, Fos expression in the SON disappeared and was partially reduced in the OVLT and MnPO. However, Fos expression did not change in the SFO. Water deprivation also 1) increased plasma renin activity (PRA), osmolality, and plasma Na+; 2) decreased blood volume; and 3) reduced total body Na+; but 4) did not alter arterial blood pressure. Rehydration with water alone caused only plasma osmolality and plasma Na+ concentration to revert to euhydrated levels. The changes in Fos expression and PRA are consistent with a proposed role for ANG II in the control of the sodium appetite produced by water deprivation followed by rehydration with only water.

Neurobiología del trastorno afectivo recurrente / Neurobiology of recurrent affective disorder

El Trastorno Afectivo Recurrente tiende a presentar, característicamente, intervalos asintomáticos sucesivamente más breves, a independizarse de estresores psicosociales y a adoptar un patrón individual de ciclicidad, con variaciones en el mismo sujeto y con respecto a otros. Estos fenómenos pueden comprenderse desde la perspectiva de vulnerabilidades experienciales, la comorbilidad con abuso de sustancias y la recurrencia de los episodios mismos, que interactuando con la vulnerabilidad genética, el grado de apoyo social y la intervención farmacológica, inducirian cambios en el balance de la expresión genética inmediata temprana y a largo plazo, relativa a la modulación del afecto y la conducta. Como ocurre esta interacción? La plasticidad neural parece crucial para el desarrollo de este tipo de aprendizaje, donde genes inmediatos tempranos como c-Fos y c-Jun, juegan un rol esencial. En este trabajo se revisan algunos aspectos básicos acerca del kindling electrofisiológico, la sensibilidad conductual, elementos generales sobre transcripción y regulación genética, además de trabajos de Robert Post sobre el tema. Considerar el Trastorno Afectivo Recurrente desde esta perspectiva podría tener importantes implicancias para la práctica clínica

Disruption of light-induced c-Fos immunoreactivity in the suprachiasmatic nuclei of chronic epileptic rats.

Photic stimulation during specific day periods may induce Fos oncoprotein expression within the ventrolateral part of the suprachiasmatic nucleus (SCN) in the hypothalamus of rodents. This phenomenon appears to be a major molecular mechanism for environmental light/dark cycle entrainment of the mammalian circadian clock. Light-dependent synchronization of circadian rhythmicity may be disrupted in epilepsy, a chronic neurological disorder often associated with chronobiological features such as seizure periodicity and disruption of endogenous biological rhythms. The present work examined the light-induced Fos protein expression on the SCN in the pilocarpine model of chronic epilepsy. Fos-like immunoreactivity was significantly reduced in the SCN of chronic epileptic rats after photic stimulation during the subjective night. These results indicate an altered Fos protein expression in the SCN of chronic epileptic rats. The present findings reveal that pathological neural events underlying epileptogenesis may disturb circadian rhythm regulation. The experimental study of circadian clock activity in the SCN may clarify the molecular bases of chronobiological disturbances in epilepsy.

Expression of c-fos and c-jun in rat retina following protracted illumination.

Illumination produces degeneration of outer photoreceptor segments, a phenomenon that may be reversed after a period of darkness. Neuronal expression of the immediate early genes (IEGs) c-fos and c-jun, both recognized as proto-oncogenes, has been reported after stimulation of different regions in the central nervous system (CNS). We performed a sequential study on Fos and Jun immunoreactivity to investigate the role of IEGs following 8 days of continuous illumination in 30-35-day-old Wistar rats. Retinas were fixed by perfusion in 4% paraformaldehyde, after a period of illumination followed by 0, 2, 7, 10 and 20 days in total darkness. Cryostat sections were immunocytochemically stained using antibodies to Fos and Jun. Fos and Jun immunoreactivities were detected in all photoreceptors evaluated, peaking in nuclei of rats kept in total darkness for 2 days, and becoming negative as from 7 days. Increases in c-fos and c-jun products during the darkness period may play a role in triggering molecular events participating in plastic changes in photoreceptors and/or in the protection for oxidative damage cause by free radicals induced by light irradiation.