Journal of Neuroendocrinology
Cara, A;Henson, E;Beekly, B;Elias, C;
| DOI: 10.1111/jne.13063
Androgens are steroid hormones that play a critical role in brain development and sexual maturation by acting upon both androgen receptors (AR), and estrogen receptors (ERα/β) after aromatization. The contribution of estrogens from aromatized androgens in brain development and the central regulation of metabolism, reproduction, and behavior is well defined, but the role of androgens acting on AR has been unappreciated. Here we map the sex specific expression of _Ar_ in the adult and developing mouse brain. Postnatal days (PND) 12 and 21 were used to target a critical window of prepubertal development. Consistent with previous literature in adults, sex-specific differences in _Ar_ expression were most profound in the bed nucleus of the stria terminalis (BST), medial amygdala (MEA), and medial preoptic area (MPO). _Ar_ expression was also high in these areas in PND 12 and 21 of both sexes. In addition, we describe extra-hypothalamic and extra-limbic areas which show moderate, consistent, and similar _Ar_ expression in both sexes at both prepubertal time points. Briefly, _Ar_ expression was observed in olfactory areas of the cerebral cortex, in the hippocampus, several thalamic nuclei, and cranial nerve nuclei involved in autonomic sensory and motor function. To further characterize forebrain populations of _Ar_ expressing neurons and determine whether they also coexpress estrogen receptors, we examined expression of _Ar_, _Esr1_, and _Esr2_ in prepubertal mice in selected nuclei. We found populations of neurons in the BST, MEA, and MPO that coexpress _Ar_, but not _Esr1_ or _Esr2_, while others express a combination of the three receptors. Our findings indicate that various brain areas express _Ar_ during prepubertal development and may play an important role in female neuronal development and physiology.
Neuroscience. 2018 Dec 26.
Manohar S, Ramchander PV, Salvi R, Seigel GM.
PMID: 30593923 | DOI: 10.1016/j.neuroscience.2018.12.023
The cochlear nucleus, located in the brainstem, receives its afferent auditory input exclusively from the auditory nerve fibers of the ipsilateral cochlea. Noise-induced neurodegenerative changes occurring in the auditory nerve stimulate a cascade of neuroplastic changes in the cochlear nucleus resulting in major changes in synaptic structure and function. To identify some of the key molecular mechanisms mediating this synaptic reorganization, we unilaterally exposed rats to a high intensity noise that caused significant hearing loss and then measured the resulting changes in a synaptic plasticity gene array targeting neurogenesis and synaptic reorganization. We compared the gene expression patterns in the dorsal cochlear nucleus (DCN) and ventral cochlear nucleus (VCN) on the noise-exposed side versus the unexposed side using a PCR gene array at 2 d (early) and 28 d (late) post-exposure. We discovered a number of differentially-expressed genes, particularly those related to synaptogenesis and regeneration. Significant gene expression changes occurred more frequently in the VCN than the DCN and more changes were seen at 28 d versus 2 d post-exposure. We confirmed the PCR findings by in situ hybridization for Brain-derived neurotrophic factor (Bdnf), Homer-1, as well as the glutamate NMDA receptor Grin1, all involved in neurogenesis and plasticity. These results suggest that Bdnf, Homer-1 and Grin1 play important roles in synaptic remodeling and homeostasis in the cochlear nucleus following severe noise-induced afferent degeneration.
Uemura, M;Furuse, T;Yamada, I;Kushida, T;Abe, T;Imai, K;Nagao, S;Kudoh, M;Yoshizawa, K;Tamura, M;Kiyonari, H;Wakana, S;Hirano, S;
PMID: 35831353 | DOI: 10.1038/s41598-022-16106-5
Protocadherin 9 (Pcdh9) is a member of the cadherin superfamily and is uniquely expressed in the vestibular and limbic systems; however, its physiological role remains unclear. Here, we studied the expression of Pcdh9 in the limbic system and phenotypes of Pcdh9-knock-out mice (Pcdh9 KO mice). Pcdh9 mRNA was expressed in the fear extinction neurons that express protein phosphatase 1 regulatory subunit 1 B (Ppp1r1b) in the posterior part of the basolateral amygdala (pBLA), as well as in the Cornu Ammonis (CA) and Dentate Gyrus (DG) neurons of the hippocampus. We show that the Pcdh9 protein was often localised at synapses. Phenotypic analysis of Pcdh9 KO mice revealed no apparent morphological abnormalities in the pBLA but a decrease in the spine number of CA neurons. Further, the Pcdh9 KO mice were related to features such as the abnormal optokinetic response, less approach to novel objects, and reduced fear extinction during recovery from the fear. These results suggest that Pcdh9 is involved in eliciting positive emotional behaviours, possibly via fear extinction neurons in the pBLA and/or synaptic activity in the hippocampal neurons, and normal optokinetic eye movement in brainstem optokinetic system-related neurons.
Neuropsychopharmacology. 2015 Jul 23.
Taylor AM, Castonguay A, Ghogha A, Vayssiere P, Pradhan AA, Xue L, Mehrabani S, Wu J, Levitt P, Olmstead MC, De Koninck Y, Evans CJ, Cahill CM.
PMID: 26202104 | DOI: 10.1038/npp.2015.221.
Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K+Cl- co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl- extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl- gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Rodriguez, LA;Kim, SH;Page, SC;Nguyen, CV;Pattie, EA;Hallock, HL;Valerino, J;Maynard, KR;Jaffe, AE;Martinowich, K;
PMID: 36369482 | DOI: 10.1038/s41386-022-01487-y
The lateral septum (LS) is a basal forebrain GABAergic region that is implicated in social novelty. However, the neural circuits and cell signaling pathways that converge on the LS to mediate social behaviors aren't well understood. Multiple lines of evidence suggest that signaling of brain-derived neurotrophic factor (BDNF) through its receptor TrkB plays important roles in social behavior. BDNF is not locally produced in LS, but we demonstrate that nearly all LS GABAergic neurons express TrkB. Local TrkB knock-down in LS neurons decreased social novelty recognition and reduced recruitment of neural activity in LS neurons in response to social novelty. Since BDNF is not synthesized in LS, we investigated which inputs to LS could serve as potential BDNF sources for controlling social novelty recognition. We demonstrate that selectively ablating inputs to LS from the basolateral amygdala (BLA), but not from ventral CA1 (vCA1), impairs social novelty recognition. Moreover, depleting BDNF selectively in BLA-LS projection neurons phenocopied the decrease in social novelty recognition caused by either local LS TrkB knockdown or ablation of BLA-LS inputs. These data support the hypothesis that BLA-LS projection neurons serve as a critical source of BDNF for activating TrkB signaling in LS neurons to control social novelty recognition.
Dembo T, Braz JM, Hamel KA, Kuhn JA, Basbaum AI.
| DOI: 10.1523/ENEURO.0402-18.2018
ABSTRACT Brain-derived neurotrophic factor (BDNF) is a critical contributor to neuronal growth, development, learning and memory. Though extensively studied in the brain, BDNF is also expressed by primary afferent sensory neurons in the peripheral nervous system. Unfortunately, anatomical and functional studies of primary afferent-derived BDNF have been limited by the availability of appropriate molecular tools. Here we used targeted, inducible molecular approaches to characterize the expression pattern of primary afferent BDNF and the extent to which it contributes to a variety of pain and itch behaviors. Using a BDNF-LacZ reporter mouse, we found that BDNF is expressed primarily by myelinated primary afferents and has limited overlap with the major peptidergic and non-peptidergic subclasses of nociceptors and pruritoceptors. We also observed extensive neuronal, but not glial, expression in the spinal cord dorsal horn. In addition, because BDNF null mice are not viable and even Cre-mediated deletion of BDNF from sensory neurons could have developmental consequences, here we deleted BDNF selectively from sensory neurons, in the adult, using an advillin-Cre-ER line crossed to floxed BDNF mice. We found that BDNF deletion in the adult altered few itch or acute and chronic pain behaviors, beyond sexually dimorphic phenotypes in the tail immersion, histamine and formalin tests. Based on the anatomical distribution of sensory neuron-derived BDNF and its limited contribution to pain and itch processing, we suggest that future studies of primary afferent-derived BDNF should examine behaviors evoked by activation of myelinated primary afferents. SIGNIFICANCE STATEMENT The neurotrophin brain-derived neurotrophic factor (BDNF) is a critical contributor to neuronal growth, development and synaptic plasticity and its expression in primary sensory neurons has been implicated in pain processing. However, there is little consensus as to the sensory neuron subtypes that express BDNF or whether sensory neuron-derived BDNF facilitates or inhibits pain generation. Here we used a BDNF reporter mouse and demonstrate that BDNF predominates in myelinated sensory neurons and is expressed in many spinal cord dorsal horn neurons. In addition, in studies in which BDNF was deleted, in the adult, from all sensory neurons, we found limited deficits in pain or itch processing.
Zahaf, A;Kassoussi, A;Hutteau-Hamel, T;Mellouk, A;Marie, C;Zoupi, L;Tsouki, F;Mattern, C;Bobé, P;Schumacher, M;Williams, A;Parras, C;Traiffort, E;
PMID: 36949062 | DOI: 10.1038/s41467-023-36846-w
Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.
Lorsch ZS, Loh YHE, Purushothaman I, Walker DM, Parise EM, Salery M ,Cahill ME, Hodes GE, Pfau ML, Kronman H, Hamilton PJ, Issler O, Labonté B, Symonds AE, Zucker M, Zhang TY, Meaney MJ, Russo SJ, Shen L, Bagot RC, Nestler EJ.
PMID: 29549264 | DOI: 10.1038/s41467-018-03567-4
Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.
bioRxiv : the preprint server for biology
François, M;Delgado, IC;Lafond, A;Lewis, EM;Kuromaru, M;Hassouna, R;Deng, S;Thaker, VV;Dölen, G;Zeltser, LM;
PMID: 36824966 | DOI: 10.1101/2023.02.15.528679
Females are more sensitive to social exclusion, which could contribute to their heightened susceptibility to anxiety disorders. Chronic social isolation stress (CSIS) for at least 7 weeks after puberty induces anxiety-related behavioral adaptations in female mice. Here, we show that Arginine vasopressin receptor 1a ( Avpr1a )-expressing neurons in the central nucleus of the amygdala (CeA) mediate these sex-specific effects, in part, via projections to the caudate putamen. Loss of function studies demonstrate that AVPR1A signaling in the CeA is required for effects of CSIS on anxiety-related behaviors in females but has no effect in males or group housed females. This sex-specificity is mediated by AVP produced by a subpopulation of neurons in the posterodorsal medial nucleus of the amygdala that project to the CeA. Estrogen receptor alpha signaling in these neurons also contributes to preferential sensitivity of females to CSIS. These data support new therapeutic applications for AVPR1A antagonists in women.
bioRxiv : the preprint server for biology
Lei, HC;Parker, KE;Yuede, CM;McCall, JG;Imai, SI;
PMID: 36711943 | DOI: 10.1101/2023.01.19.524624
Age-associated reduced motivation is a hallmark of neuropsychiatric disorders in the elderly. In our rapidly aging societies, it is critical to keep motivation levels high enough to promote healthspan and lifespan. However, how motivation is reduced during aging remains unknown. Here, we used multiple mouse models to evaluate motivation and related affective states in young and old mice. We also compared the effect of social isolation, a common stressor, to those of aging. We found that both social isolation and aging decreased motivation in mice, but that Bdnf expression in the ventral tegmental area (VTA) was selectively decreased during aging. Furthermore, VTA-specific Bdnf knockdown in young mice recapitulated reduced motivation observed in old mice. These results demonstrate that maintaining Bdnf expression in the VTA could promote motivation to engage in effortful activities and potentially prevent age-associated neuropsychiatric disorders.
BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury
Huang, L;Jin, J;Chen, K;You, S;Zhang, H;Sideris, A;Norcini, M;Recio-Pinto, E;Wang, J;Gan, WB;Yang, G;
PMID: 34292944 | DOI: 10.1371/journal.pbio.3001337
Peripheral nerve injury-induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury-induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.
Proc Natl Acad Sci U S A.
Shen H, Marino RAM, McDevitt RA, Bi GH, Chen K, Madeo G, Lee PT, Liang Y, De Biase LM, Su TP, Xi ZX, Bonci A.
PMID: 30442663 | DOI: 10.1073/pnas.1800886115
A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.
