Gender Differences in the Neurobiology of Anxiety: Focus on Adult Hippocampal Neurogenesis.

Although the literature reports a higher incidence of anxiety disorders in women, the majority of basic research has focused on male rodents, thus resulting in a lack of knowledge on the neurobiology of anxiety in females. Bridging this gap is crucial for the design of effective translational interventions in women. One of the key brain mechanisms likely to regulate anxious behavior is adult hippocampal neurogenesis (AHN). This review paper aims to discuss the evidence on the differences between male and female rodents with regard to anxiety-related behavior and physiology, with a special focus on AHN. The differences between male and female physiologies are greatly influenced by hormonal differences. Gonadal hormones and their fluctuations during the estrous cycle have often been identified as agents responsible for sexual dimorphism in behavior and AHN. During sexual maturity, hormone levels fluctuate cyclically in females more than in males, increasing the stress response and the susceptibility to anxiety. It is therefore of great importance that future research investigates anxiety and other neurophysiological aspects in the female model, so that results can be more accurately applicable to the female population.

Retinal development impairment and degenerative alterations in adult rats subjected to post-natal malnutrition.

BACKGROUND: The early stages of central nervous system (CNS) development are extremely important. Key events such as neurogenesis, gliogenesis, synaptogenesis, and ontogenesis occur. Malnutrition promotes alterations in CNS development, including the retinal development. During retinal development, malnutrition can induce a delay in some important events, such as neurotransmitter expression and neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Postpartum Wistar rats were fed either a commercial diet or a multideficient diet. Pups were breastfed by these rats, and from PND21 were kept with the same diet until PND45. We investigated the effects of malnutrition on adult retinal tissue with regard to (1) endogenous gamma-amino butyric acid (GABA) release induced by excitatory amino acids (EAAs) and (2) the expression of cellular markers related to degenerative events, such as reactive gliosis, microglial activation, cell proliferation and cell death. Endogenous GABA release induced by EAAs was higher in the retina of malnourished rats. The Müller cell population was reduced and displayed alterations in their phenotype profile compatible with reactive gliosis. The expression of glutamine synthetase and markers of cellular proliferation were higher in the retina of malnourished rats. Additionally, retinal dysplasia-like structures were present, indicating disturbance in the cell cycle machinery. CONCLUSION/SIGNIFICANCE: The current study provides evidence that the adult retina shows degenerative processes induced by long-term malnutrition during the postnatal development. These findings have high clinical significance with regard to the identification of possible targets for interventions in malnourished patients.

Hippocampal biomarkers of fear memory in an animal model of generalized anxiety disorder.

Generalized anxiety disorder (GAD) is highly prevalent and incapacitating. Here we used the Carioca High-Conditioned Freezing (CHF) rats, a previously validated animal model for GAD, to identify biomarkers and structural changes in the hippocampus that could be part of the underlying mechanisms of their high-anxiety profile. Spatial and fear memory was assessed in the Morris water maze and passive avoidance test. Serum corticosterone levels, immunofluorescence for glucocorticoid receptors (GR) in the dentate gyrus (DG), and western blotting for hippocampal brain derived neurotrophic factor (BDNF) were performed. Immunohistochemistry for markers of cell proliferation (bromodeoxiuridine/Ki-67), neuroblasts (doublecortin), and cell survival were undertaken in the DG, along with spine staining (Golgi) and dendritic arborization tracing. Hippocampal GABA release was assessed by neurochemical assay. Fear memory was higher among CHF rats whilst spatial learning was preserved. Serum corticosterone levels were increased, with decreased GR expression. No differences were observed in hippocampal cell proliferation/survival, but the number of newborn neurons was decreased, along with their number and length of tertiary dendrites. Increased expression of proBDNF and dendritic spines was observed; lower ratio of GABA release in the hippocampus was also verified. These findings suggest that generalized anxiety/fear could be associated with different hippocampal biomarkers, such as increased spine density, possibly as a compensatory mechanism for the decreased hippocampal number of neuroblasts and dendritic arborization triggered by high corticosterone. Disruption of GABAergic signaling and BDNF impairment are also proposed as part of the hippocampal mechanisms possibly underlying the anxious phenotype of this model.

Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms.

The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients.

Bipolar disorder and Premenstrual Syndrome or Premenstrual Dysphoric Disorder comorbidity: a systematic review / Comorbidade entre o Transtorno Bipolar e Síndrome Pré-menstrual ou Transtorno Disfórico Pré-menstrual: uma revisão sistemática

OBJECTIVE: This article aims to review the comorbidity of premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) and bipolar disorder (BD), identify variables requiring further investigation and to remind physicians that special care is required for diagnosis and therapy. METHOD: A systematic review of articles published from 1987 to February 2012 was conducted in the Medline database with the following terms: (premenstrual syndrome OR premenstrual dysphoric disorder OR premenstrual) AND (bipolar OR mania OR manic). Seventeen articles were analyzed. RESULTS: PMS and PMDD were most often comorbid among BD-II patients and vice versa. Moreover, patients with PMS or PMDD also have an increased risk of having BD-I. In addition, bipolar women susceptible to hormonal changes exhibit more severe symptoms, more frequent relapses and a worse therapeutic response. CONCLUSION: Future investigations should attempt to stabilize hormonal levels through the continuous use of contraceptives to target a reduction in symptom severity. In addition, psychiatrists should note menstrual period dates and compare symptom intensity between the luteal and follicular phases. Finally, PMS and PMDD patients should be studied separately.

OBJETIVO: Esse artigo tem como objetivo revisar a comorbidade entre a Síndrome Pré-Menstrual (SPM) ou Transtorno Disfórico Pré-Menstrual (TDPM) e o Transtorno Bipolar (TB), identificar as variáveis que exigem uma investigação mais aprofundada e lembrar os médicos que as mulheres necessitam de cuidados especiais para diagnóstico e tratamento. MÉTODO: Foi realizada uma revisão sistemática de 1987 a fevereiro de 2012 através da base de dados Medline utilizando os seguintes descritores: (premenstrual syndrome OR premenstrual dysphoric disorder OR premenstrual) AND (bipolar OR mania OR manic). Dezessete artigos foram analisados. RESULTADOS: Pacientes com SPM ou TDPM possuem comorbidade com TB-II com maior frequência e vice-versa. Mulheres com SPM ou TDPM também possuem um risco aumentado apresentar TB-I. Além disso, as mulheres bipolares suscetíveis a mudanças hormonais cursam com sintomas mais graves, recaídas mais freqüentes e pior resposta terapêutica. CONCLUSÃO: Futuras investigações devem estabilizar os níveis hormonais com o uso contínuo de contraceptivos na tentativa de diminuir a gravidade dos sintomas. Além disso, psiquiatras devem observar os períodos menstruais e comparar a intensidade dos sintomas entre as fases folicular e lútea. Pacientes com SPM ou TDPM devem ser estudadas separadamente.

Bipolar disorder and Premenstrual Syndrome or Premenstrual Dysphoric Disorder comorbidity: a systematic review.

OBJECTIVE: This article aims to review the comorbidity of premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) and bipolar disorder (BD), identify variables requiring further investigation and to remind physicians that special care is required for diagnosis and therapy. METHOD: A systematic review of articles published from 1987 to February 2012 was conducted in the Medline database with the following terms: (premenstrual syndrome OR premenstrual dysphoric disorder OR premenstrual) AND (bipolar OR mania OR manic). Seventeen articles were analyzed. RESULTS: PMS and PMDD were most often comorbid among BD-II patients and vice versa. Moreover, patients with PMS or PMDD also have an increased risk of having BD-I. In addition, bipolar women susceptible to hormonal changes exhibit more severe symptoms, more frequent relapses and a worse therapeutic response. CONCLUSION: Future investigations should attempt to stabilize hormonal levels through the continuous use of contraceptives to target a reduction in symptom severity. In addition, psychiatrists should note menstrual period dates and compare symptom intensity between the luteal and follicular phases. Finally, PMS and PMDD patients should be studied separately.

Current methodological designs of fMRI studies of panic disorder: can data be compared?

Panic disorder (PD) is a pluridimensional condition that leads to psychological suffering. Due to advances in neuroimaging techniques, important contributions have been made in the understanding of the neurobiological basis of PD. However, because of diverging research designs and protocols, more conclusive data concerning the neurocircuitry of PD remain difficult to achieve. To address this issue, a bibliographical search was performed using the Institute for Scientific Information Web of Science and Medline/PubMed databases. Fifteen articles were found, and their research methodology including sample, comorbidity, gender, and pharmacological criteria were explored. Although current functional magnetic resonance imaging studies of PD constitute fundamental tools for health sciences, more uniform research protocols must be implemented to provide more consistent and conclusive data concerning the neural substrates of PD.

Current methodological designs of fMRI studies of panic disorder: can data be compared?

Panic disorder (PD) is a pluridimensional condition that leads to psychological suffering. Due to advances in neuroimaging techniques, important contributions have been made in the understanding of the neurobiological basis of PD. However, because of diverging research designs and protocols, more conclusive data concerning the neurocircuitry of PD remain difficult to achieve. To address this issue, a bibliographical search was performed using the Institute for Scientific Information Web of Science and Medline/PubMed databases. Fifteen articles were found, and their research methodology including sample, comorbidity, gender, and pharmacological criteria were explored. Although current functional magnetic resonance imaging studies of PD constitute fundamental tools for health sciences, more uniform research protocols must be implemented to provide more consistent and conclusive data concerning the neural substrates of PD.(AU)

Current findings of fMRI in panic disorder: contributions for the fear neurocircuitry and CBT effects.

Thanks to brain imaging great advances have been made concerning the comprehension of neural substrates related to panic disorder (PD). This article aims to: review the recent functional MRI (fMRI) studies concerning PD; correlate the PD fMRI neurobiological findings with the fear neurocircuitry hypothesis; discuss the fear neurocircuitry hypothesis and link it to cognitive-behavior therapy findings; and comment on fMRI study limitations and suggest methodological changes for future research. As a whole, there is increasing evidence that brain structures such as the prefrontal cortex, the anterior cingulate cortex and limbic areas (hippocampus and amygdala) might play a major role in the panic response.

Behavioral profile and dorsal hippocampal cells in carioca high-conditioned freezing rats.

Selection for contextual fear conditioning is an important behavioral paradigm for studying the role of genetic variables and their interaction with the surrounding environment in the etiology and development of anxiety disorders. Recently, a new line of animals selectively bred for high levels of freezing in response to contextual cues previously associated with footshock was developed from a Wistar population. The purpose of the present study was to evaluate the emotional and cognitive aspects of this new line of animals, which has been named Carioca High-Freezing (CHF). For the characterization of anxious behavior, CHF and control animals were tested in the elevated plus-maze (EPM) and the social interaction test. CHF animals were significantly more anxious than control rats in terms of both the number of entries into EPM open arms and the percentage of time spent in these arms. The time spent in social interaction behavior was also significantly decreased. No statistical differences were found in locomotor activity, as measured by both the number of entries into the closed arms of the EPM and the number of crossings into the social interaction test arena. No differences between CHF and control groups were found in the depression forced swimming test, suggesting that the anxiety trait selected in the CHF line did not interact with affective disorders traits such as those for depression. Cognitive aspects of the CHF rats were evaluated in the object recognition task. Results from this test indicated no difference between the two groups. The present study also encompassed histological analysis of the dorsal hippocampus from CHF and control animals. Results revealed an absence of qualitative and quantitative differences between these two groups of animals in cells located in the dentate gyrus, CA1, and CA3 areas. Therefore, future studies are required to further investigate the possible neural mechanisms involved in the origin and development of the anxious phenotype observed in this model.