Dopamine Neuron Activity and Stress Signaling as Links Between Social Hierarchy and Psychopathology Vulnerability.

BACKGROUND: Social status in humans, generally reflected by socioeconomic status, has been associated, when constrained, with heightened vulnerability to pathologies including psychiatric diseases. Social hierarchy in mice translates into individual and interdependent behavioral strategies of animals within a group. The rules leading to the emergence of a social organization are elusive, and detangling the contribution of social status from other factors, whether environmental or genetic, to normal and pathological behaviors remains challenging. METHODS: We investigated the mechanisms shaping the emergence of a social hierarchy in isogenic C57BL/6 mice raised in groups of 4 using conditional mutant mouse models and chemogenetic manipulation of dopamine midbrain neuronal activity. We further studied the evolution of behavioral traits and the vulnerability to psychopathological-like phenotypes according to the social status of the animals. RESULTS: Higher sociability predetermined higher social hierarchy in the colony. Upon hierarchy establishment, higher-ranked mice showed increased anxiety and better cognitive abilities in a working memory task. Strikingly, the higher-ranked mice displayed a reduced activity of dopaminergic neurons within the ventral tegmental area, paired with a decreased behavioral response to cocaine and a decreased vulnerability to depressive-like behaviors following repeated social defeats. The pharmacogenetic inhibition of this neuronal population and the genetic inactivation of glucocorticoid receptor signaling in dopamine-sensing brain areas that resulted in decreased dopaminergic activity promoted accession to higher social ranks. CONCLUSIONS: Dopamine activity and its modulation by the stress response shapes social organization in mice, potentially linking interindividual and social status differences in vulnerability to psychopathologies.

SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress.

Enduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

The glucocorticoid receptor in the nucleus accumbens plays a crucial role in social rank attainment in rodents.

Social hierarchy in social species is usually established through competitive encounters with conspecifics. It determines the access to limited resources and, thus, leads to reduced fights among individuals within a group. Despite the known importance of social rank for health and well-being, the knowledge about the processes underlying rank attainment remains limited. Previous studies have highlighted the nucleus accumbens (NAc) as a key brain region in the attainment of social hierarchies in rodents. In addition, glucocorticoids and the glucocorticoid receptor (GR) have been implicated in the establishment of social hierarchies and social aversion. However, whether GR in the NAc is involved in social dominance is not yet known. To address this question, we first established that expression levels of GR in the NAc of high anxious, submissive-prone rats are lower than that of their low anxious, dominant-prone counterparts. Furthermore, virally-induced downregulation of GR expression in the NAc in rats led to an improvement of social dominance rank. We found a similar result in a cell-specific mouse model lacking GR in dopaminoceptive neurons (i.e., neurons containing dopamine receptors). Indeed, when cohabitating in dyads of mixed genotypes, mice deficient for GR in dopaminoceptive neurons had a higher probability to become dominant than wild-type mice. Overall, our results highlight GR in the NAc and in dopaminoceptive neurons as an important regulator of social rank attainment.

Dlx5 and Dlx6 expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan.

Dlx5 and Dlx6 encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development, Dlx5/6 play a role in the differentiation of certain GABAergic subclasses. Here we address the question of the functional role of Dlx5/6 in the mature central nervous system. First, we demonstrate that Dlx5 and Dlx6 are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyze VgatΔDlx5-6 mice in which Dlx5 and Dlx6 are simultaneously inactivated in all GABAergic interneurons. VgatΔDlx5-6 mice present a behavioral pattern suggesting reduction of anxiety-like behavior and obsessive-compulsive activities, and a lower interest in nest building. Twenty-month-old VgatΔDlx5-6 animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, both VgatΔDlx5-6/+ and VgatΔDlx5-6 mice present a 33% longer median survival. Hallmarks of biological aging such as motility, adiposity and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate healthspan and lifespan through Dlx5/6-dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.

Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity.

The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson's disease (PD) is not well characterized. In this study, using GRCx30CreERT2 mice that are conditionally inactivated for glucocorticoid receptor (GR) in astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show significantly augmented DN loss in GRCx30CreERT2 mutant mice in substantia nigra (SN) compared to controls. Hypertrophy of microglia but not of astrocytes was greatly enhanced in SN of these astrocytic GR mutants intoxicated with MPTP, indicating heightened microglial reactivity compared to similarly-treated control mice. In the SN of GR astrocyte mutants, specific inflammation-associated transcripts ICAM-1, TNF-α and Il-1ß as well as TNF-α protein levels were significantly elevated after MPTP neurotoxicity compared to controls. Interestingly, this paralleled increased connexin hemichannel activity and elevated intracellular calcium levels in astrocytes examined in acute midbrain slices from control and mutant mice treated with MPP+ . The increased connexin-43 hemichannel activity was found in vivo in MPTP-intoxicated mice. Importantly, treatment of MPTP-injected GRCx30CreERT2 mutant mice with TAT-Gap19 peptide, a specific connexin-43 hemichannel blocker, reverted both DN loss and microglial activation; in wild-type mice there was partial but significant survival effect. In the SN of post-mortem PD patients, a significant decrease in the number of astrocytes expressing nuclear GR was observed, suggesting the participation of astrocytic GR deregulation of inflammatory process in PD. Overall, these data provide mechanistic insights into GR-modulated processes in vivo, specifically in astrocytes, that contribute to a pro-inflammatory state and dopamine neurodegeneration in PD pathology.

Author Correction: TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons.

The originally published version of this Article contained an error in the subheading "Microglial GR does not affect DN loss triggered by TLR4 and TLR7," which was incorrectly given as "Microglial GR does affect DN loss triggered by TLR2 and TLR4". This has now been corrected in both the PDF and HTML versions of the Article.

Identification of an acute functional cross-talk between amyloid-ß and glucocorticoid receptors at hippocampal excitatory synapses.

Amyloid-ß is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-ß (Aßο) is now believed to represent the main Amyloid-ß species affecting synapse function. Yet, the exact molecular mechanism by which Aßο modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Aßο generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Aß and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Aßo (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Aßo-mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Aßo-mediated LTP impairment, but not Aßo-mediated LTD induction. The necessity of neuronal GRs for Aßo-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Aß activities at excitatory synapses.

TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons.

Inflammation is a characteristic feature of Parkinson's disease (PD). We examined the role of TLR9 and its regulation by glucocorticoid receptors (GRs) in degeneration of substantia nigra dopamine neurons (DNs). TLR9 agonist, CpG-ODN, induced DN degeneration in mice lacking GR in microglia but not in controls. TLR9 deletion reduced DN loss in neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. GR regulates TLR9 activation during MPTP neurotoxicity as TLR9 antagonist suppressed increased DN loss in microglia/macrophage GR mutant mice. GR absence in microglia enhanced TLR9 translocation to endolysosomes and facilitated its cleavage leading to pro-inflammatory gene expression. GR-dependent TLR9 activation also triggered DN loss following intranigral injection of mitochondrial DNA. Finally, microglial GR sensitivity to A53T-alpha-synuclein induced DN degeneration as well as decreased microglial GR expression observed in SN of PD brain samples, all suggest that reduced microglial GR activity in SN can stimulate TLR9 activation and DN loss in PD pathology.

The GABAergic Gudden's dorsal tegmental nucleus: A new relay for serotonergic regulation of sleep-wake behavior in the mouse.

Serotonin (5-HT) neurons are involved in wake promotion and exert a strong inhibitory influence on rapid eye movement (REM) sleep. Such effects have been ascribed, at least in part to the action of 5-HT at post-synaptic 5-HT1A receptors (5-HT1AR) in the brainstem, a major wake/REM sleep regulatory center. However, the neuroanatomical substrate through which 5-HT1AR influence sleep remains elusive. We therefore investigated whether a brainstem structure containing a high density of 5-HT1AR mRNA, the GABAergic Gudden's dorsal tegmental nucleus (DTg), may contribute to 5-HT-mediated regulatory mechanisms of sleep-wake stages. We first found that bilateral lesions of the DTg promote wake at the expense of sleep. In addition, using local microinjections into the DTg in freely moving mice, we showed that local activation of 5-HT1AR by the prototypical agonist 8-OH-DPAT enhances wake and reduces deeply REM sleep duration. The specific involvement of 5-HT1AR in the latter effects was further demonstrated by ex vivo extracellular recordings showing that the selective 5-HT1AR antagonist WAY 100635 prevented DTg neuron inhibition by 8-OH-DPAT. We next found that GABAergic neurons of the ventral DTg exclusively targets glutamatergic neurons of the lateral mammillary nucleus (LM) in the posterior hypothalamus by means of anterograde and retrograde tracing techniques using cre driver mouse lines and a modified rabies virus. Altogether, our findings strongly support the idea that 5-HT-driven enhancement of wake results from 5-HT1AR-mediated inhibition of DTg GABAergic neurons that would in turn disinhibit glutamatergic neurons in the mammillary bodies. We therefore propose a Raphe→DTg→LM pathway as a novel regulatory circuit underlying 5-HT modulation of arousal.

Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson's disease-like non-motor symptoms without loss of dopamine neurons.

Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson's disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson's disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons (Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson's disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson's disease and reduces dopamine content in the absence of dopamine neuron loss.

Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin.

Insulin-like growth factors control numerous processes, namely somatic growth, metabolism and stress resistance, connecting this pathway to aging and age-related diseases. Insulin-like growth factor signaling also impacts on neurogenesis, neuronal survival and structural plasticity. Recent reports demonstrated that diminished insulin-like growth factor signaling confers increased stress resistance in brain and other tissues. To better understand the role of neuronal insulin-like growth factor signaling in neuroprotection, we inactivated insulin-like growth factor type-1-receptor in forebrain neurons using conditional Cre-LoxP-mediated gene targeting. We found that brain structure and function, including memory performance, were preserved in insulin-like growth factor receptor mutants, and that certain characteristics improved, notably synaptic transmission in hippocampal neurons. To reveal stress-related roles of insulin-like growth factor signaling, we challenged the brain using a stroke-like insult. Importantly, when charged with hypoxia-ischemia, mutant brains were broadly protected from cell damage, neuroinflammation and cerebral edema. We also found that in mice with insulin-like growth factor receptor knockout specifically in forebrain neurons, a substantial systemic upregulation of growth hormone and insulin-like growth factor-I occurred, which was associated with significant somatic overgrowth. Collectively, we found strong evidence that blocking neuronal insulin-like growth factor signaling increases peripheral somatotropic tone and simultaneously protects the brain against hypoxic-ischemic injury, findings that may contribute to developing new therapeutic concepts preventing the disabling consequences of stroke.

Correction: Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells.

[This corrects the article DOI: 10.1371/journal.pone.0149343.].

Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration.

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells.

Diabetes is a major complication of chronic Glucocorticoids (GCs) treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1) and 2 (Tph2), leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells.

Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo.

Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson's disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.

Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus.

BACKGROUND: Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. METHODS: Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. RESULTS: Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. CONCLUSIONS: Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders.

Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine.

The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs) release. GCs bind the glucocorticoid receptor (GR) a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While GR within dopamine-innervated areas drives cocaine's behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

Plasticity of hypothalamic dopamine neurons during lactation results in dissociation of electrical activity and release.

Tuberoinfundibular dopamine (TIDA) neurons are the central regulators of prolactin (PRL) secretion. Their extensive functional plasticity allows a change from low PRL secretion in the non-pregnant state to the condition of hyperprolactinemia that characterizes lactation. To allow this rise in PRL, TIDA neurons are thought to become unresponsive to PRL at lactation and functionally silenced. Here we show that, contrary to expectations, the electrical properties of the system were not modified during lactation and that the neurons remained electrically responsive to a PRL stimulus, with PRL inducing an acute increase in their firing rate during lactation that was identical to that seen in non-pregnant mice. Furthermore, we show a long-term organization of TIDA neuron electrical activity with an harmonization of their firing rates, which remains intact during lactation. However, PRL-induced secretion of dopamine (DA) at the median eminence was strongly blunted during lactation, at least in part attributable to lack of phosphorylation of tyrosine hydroxylase, the key enzyme involved in DA synthesis. We therefore conclude that lactation, rather than involving electrical silencing of TIDA neurons, represents a condition of decoupling between electrical activity at the cell body and DA secretion at the median eminence.

The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination.

Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7α-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis.

Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons.

Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.