Gisele Pereira Dias

Effects of diet on brain plasticity in animal and human studies: mind the gap.

Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake), intermittent fasting (IF, every-other-day feeding), and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs) on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting the effects of CR, IF and dietary polyphenols and PUFAs on learning, memory, and mood. In particular, we evaluate the gap in mechanistic understanding between recent findings from animal studies and those human studies reporting that these dietary factors can benefit cognition, mood, and anxiety, aging, and Alzheimers disease—with focus on the enhancement of structural and functional plasticity markers in the hippocampus, such as increased expression of neurotrophic factors, synaptic function and adult neurogenesis. Lastly, we discuss some of the obstacles to harnessing the promising effects of diet on brain plasticity in animal studies into effective recommendations and interventions to promote healthy brain function in humans. Together, these data reinforce the important translational concept that diet, a modifiable lifestyle factor, holds the ability to modulate brain health and function.

The Role of Dietary Polyphenols on Adult Hippocampal Neurogenesis: Molecular Mechanisms and Behavioural Effects on Depression and Anxiety

Although it has been long believed that new neurons were only generated during development, there is now growing evidence indicating that at least two regions in the brain are capable of continuously generating functional neurons: the subventricular zone and the dentate gyrus of the hippocampus. Adult hippocampal neurogenesis (AHN) is a widely observed phenomenon verified in different adult mammalian species including humans. Factors such as environmental enrichment, voluntary exercise, and diet have been linked to increased levels of AHN. Conversely, aging, stress, anxiety and depression have been suggested to hinder it. However, the mechanisms underlying these effects are still unclear and yet to be determined. In this paper, we discuss some recent findings addressing the effects of different dietary polyphenols on hippocampal cell proliferation and differentiation, models of anxiety, and depression as well as some proposed molecular mechanisms underlying those effects with particular focus on those related to AHN. As a whole, dietary polyphenols seem to exert positive effects on anxiety and depression, possibly in part via regulation of AHN. Studies on the effects of dietary polyphenols on behaviour and AHN may play an important role in the approach to use diet as part of the therapeutic interventions for mental-health-related conditions.

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.

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.

Consequences of cancer treatments on adult hippocampal neurogenesis

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.

A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine.

Abstract This long-term extension of an 8-week randomized, naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam (n = 47) and paroxetine (n = 37) over a 3-year total treatment duration. Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine (both taken at bedtime). This study reports data from the long-term period (34 months), following the initial 8-week treatment phase. Thus, total treatment duration was 36 months. Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine, but patients with partial primary treatment success were switched to the combination therapy. At initiation of the long-term study, the mean doses of clonazepam and paroxetine were 1.9 (SD, 0.30) and 38.4 (SD, 3.74) mg/d, respectively. These doses were maintained until month 36 (clonazepam 1.9 [SD, 0.29] mg/d and paroxetine 38.2 [SD, 3.87] mg/d). Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)–Improvement rating than treatment with paroxetine (mean difference: CGI-Severity scale −3.48 vs −3.24, respectively, P = 0.02; CGI-Improvement scale 1.06 vs 1.11, respectively, P = 0.04). Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine (28.9% vs 70.6%, P < 0.001). The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course. There was a significant advantage with clonazepam over paroxetine with respect to the frequency and nature of adverse events.

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.

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.

Current concept of anxiety: implications from Darwin to the DSM-V for the diagnosis of generalized anxiety disorder

This article proposes a revision of the historical evolution of the concepts of generalized anxiety disorder (GAD). Currently, Darwin’s evolutionary theory is the hegemonic paradigm for modern science and influences research on mental disorders. Throughout the 20th Century, the editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM; American Psychiatric Association) have changed the diagnostic criteria for GAD, reflecting the prevailing psychiatric understanding of this disorder. The prevalence and symptoms of major depression and GAD show the fragility of the categorical conception of these conditions. Differences in cultural views towards anxiety disorders also suggest that anxiety cannot have a uniform definition. This article provides contributions for reflecting future guidelines concerning the diagnostic criteria for GAD in DSM-V.

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.