Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects

Although neurotrophins have been postulated to have antidepressant properties, their effect on anxiety is not clear. We find that transgenic overexpression of the neurotrophin BDNF has an unexpected facilitatory effect on anxiety-like behavior, concomitant with increased spinogenesis in the basolateral amygdala. Moreover, anxiogenesis and amygdalar spinogenesis are also triggered by chronic stress in control mice but are occluded by BDNF overexpression, thereby suggesting a role for BDNF signaling in stress-induced plasticity in the amygdala. BDNF overexpression also causes antidepressant effects, because transgenic mice exhibit improved performance on the Porsolt forced-swim test and an absence of chronic stress-induced hippocampal atrophy. Thus, structural changes in the amygdala and hippocampus, caused by genetic manipulation of the same molecule BDNF, give rise to contrasting effects on anxiety and depressive symptoms, both of which are major behavioral correlates of stress disorders

Experiential contributions to social dominance in a rat model of Fragile-X syndrome

Social withdrawal is one phenotypic feature of the monogenic neurodevelopmental disorder Fragile-X. Using a ‘knock-out’ rat model of Fragile-X, we examined whether deletion of the Fmr1 gene that causes this condition would affect the ability to form and express a social hierarchy as measured in a tube-test. Male Fragile-X ‘knock-out’ rats living together could successfully form a social dominance hierarchy, but were significantly subordinate to wild-type animals in mixed group cages. Over 10 days of repeated testing, the Fragile-X mutant rats gradually showed greater variance and instability of rank during their tube-test encounters. This affected the outcome of future encounters with stranger animals from other cages, with the initial phenotype of wild-type dominance lost to a more complex picture that reflected, regardless of genotype, the prior experience of winning or losing. Our findings offer a novel insight into the complex dynamics of social interactions between laboratory living groups of Fragile X and wild-type rats. Even though this is a monogenic condition, experience has an impact upon future interactions with other animals. Gene/environment interactions should therefore be considered in the development of therapeutics

Ca2+ imaging of self and other in medial prefrontal cortex during social dominance interactions in a tube test.

The study of social dominance interactions between animals offers a window onto the decision-making involved in establishing dominance hierarchies and an opportunity to examine changes in social behavior observed in certain neurogenetic disorders. Competitive social interactions, such as in the widely used tube test, reflect this decision-making. Previous studies have focused on the different patterns of behavior seen in the dominant and submissive animal, neural correlates of effortful behavior believed to mediate the outcome of such encounters, and interbrain correlations of neural activity. Using a rigorous mutual information criterion, we now report that neural responses recorded with endoscopic calcium imaging in the prelimbic zone of the medial prefrontal cortex show unique correlations to specific dominance-related behaviors. Interanimal analyses revealed cell/behavior correlations that are primarily with an animal's own behavior or with the other animal's behavior, or the coincident behavior of both animals (such as pushing by one and resisting by the other). The comparison of unique and coincident cells helps to disentangle cell firing that reflects an animal's own or the other's specific behavior from situations reflecting conjoint action. These correlates point to a more cognitive rather than a solely behavioral dimension of social interactions that needs to be considered in the design of neurobiological studies of social behavior. These could prove useful in studies of disorders affecting social recognition and social engagement, and the treatment of disorders of social interaction

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3-/y rat model of autism

Abstract Background Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. Methods This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3 −/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3 −/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results We observed that, unlike the wildtype, Nlgn3 −/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3 −/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3 −/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. Conclusions We describe altered fear responses in Nlgn3 −/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD

'Memories of a lost war' A study of American poetic responses to the Vietnam War

SIGLEAvailable from British Library Document Supply Centre-DSC:D203661 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

PROLONGED BEHAVIORAL STRESS ENHANCES SYNAPTIC CONNECTIVITY IN THE BASOLATERAL AMYGDALA

Abstract-Recently identified cellular and molecular correlates of stress-induced plasticity suggest a putative link between neuronal remodeling in the amygdala and the development of anxiety-like behavior. Rodent models of immobilization stress, applied for 10 consecutive days, have been reported to enhance anxiety, and also cause dendritic elongation and spine formation in the basolateral amygdala (BLA). Paradoxically, longer exposure to stress, which is also anxiogenic, fails to affect key molecular markers of neuronal remodeling in the BLA. This has raised the possibility of homeostatic mechanisms being triggered by more prolonged stress that could potentially dampen the morphological effects of stress in the BLA. Therefore, we examined the cellular and behavioral impact of increasing the duration of stress in rats. We find that prolonged immobilization stress (PIS), spanning 21 days, caused significant enhancement in dendritic arborization of spiny BLA neurons. Spine density was also enhanced along these elongated dendrites in response to PIS. Finally, this striking increase in synaptic connectivity was accompanied by enhanced anxiety-like behavior in the elevated plus-maze. Thus, we did not detect any obvious morphological correlate of adaptive changes within the BLA that may have been activated by prolonged and repeated application of the same stressor for 21 days. These findings add to accumulating evidence that structural encoding of aversive experiences, through enhanced availability of postsynaptic dendritic surface and synaptic inputs on principal neurons of the BLA, may contribute to the affective symptoms of stress disorders

Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala

Recently identified cellular and molecular correlates of stress-induced plasticity suggest a putative link between neuronal remodeling in the amygdala and the development of anxiety-like behavior. Rodent models of immobilization stress, applied for 10 consecutive days, have been reported to enhance anxiety, and also cause dendritic elongation and spine formation in the Basolateral Amygdala (BLA). Paradoxically, longer exposure to stress, which is also anxiogenic, fails to affect key molecular markers of neuronal remodeling in the BLA. This has raised the possibility of homeostatic mechanisms being triggered by more prolonged stress that could potentially dampen the morphological effects of stress in the BLA. Therefore, we examined the cellular and behavioral impact of increasing the duration of stress in rats. We find that Prolonged Immobilization Stress (PIS), spanning 21 days, caused significant enhancement in dendritic arborization of spiny BLA neurons. Spine density was also enhanced along these elongated dendrites in response to PIS. Finally, this striking increase in synaptic connectivity was accompanied by enhanced anxiety-like behavior in the elevated plus-maze. Thus, we did not detect any obvious morphological correlate of adaptive changes within the BLA that may have been activated by prolonged and repeated application of the same stressor for 21 days. These findings add to accumulating evidence that structural encoding of aversive experiences, through enhanced availability of postsynaptic dendritic surface and synaptic inputs on principal neurons of the BLA, may contribute to the affective symptoms of stress disorders

Stress, memory and the amygdala

Emotionally significant experiences tend to be well remembered, and the amygdala has a pivotal role in this process. But the efficient encoding of emotional memories can become maladaptive - severe stress often turns them into a source of chronic anxiety. Here, we review studies that have identified neural correlates of stress-induced modulation of amygdala structure and function - from cellular mechanisms to their behavioural consequences. The unique features of stress-induced plasticity in the amygdala, in association with changes in other brain regions, could have long-term consequences for cognitive performance and pathological anxiety exhibited in people with affective disorders