Temporal discrimination from the interaction between dynamic synapses and intrinsic subthreshold oscillations

The interaction between synaptic and intrinsic dynamics can efficiently shape neuronal input-output relationships in response to temporally structured spike trains. We use a neuron model with subthresh-old oscillations receiving inputs through a synapse with short-term depression and facilitation to show that the combination of intrinsic subthreshold and synaptic dynamics leads to channel-specific nontrivial responses and recognition of specific temporal structures. Our study employs the Generalized Integrate and-Fire (GIF) model, which can be subjected to analytical characterization. We map the temporal structure of spike input trains to the type of spike response, and show how the emergence of nontrivial input- output preferences is modulated by intrinsic and synaptic parameters in a synergistic manner. We demonstrate that these temporal input discrimination properties are robust to noise and to variations in synaptic strength. Furthermore, we also illustrate the presence of these input-output relationships in conductance-based models. Our results suggest a widespread computationally economic and easily tunable mechanism for temporal information discrimination in single neurons. (c) 2020 Elsevier B.V. All rights reserved.This work was supported AEI/FEDER grants FIS2017-84256-P (JJT) and PGC2018-095895-B-I00, DPI2015-65833-P (RL & PV)

Reliability of Eye Tracking and Pupillometry Measures in Individuals with Fragile X Syndrome

Recent insight into the underlying molecular and cellular mechanisms of fragile X syndrome (FXS) has led to the proposal and development of new pharmaceutical treatment strategies, and the initiation of clinical trials aimed at correcting core symptoms of the developmental disorder. Consequently, there is an urgent and critical need for outcome measures that are valid for quantifying specific symptoms of FXS and that are consistent across time. We used eye tracking to evaluate test–retest reliability of gaze and pupillometry measures in individuals with FXS and we demonstrate that these measures are viable options for assessing treatment-specific outcomes related to a core behavioral feature of the disorder

Median raphe region stimulation alone generates remote, but not recent fear memory traces

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex

FMR1 premutation and full mutation molecular mechanisms related to autism

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism

Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review

Fragile X Syndrome (FXS) is characterised by features including anxiety and autistic-like behaviour, which led to early hypotheses that aberrant physiological arousal may underlie the behavioural phenotype. In line with this, several lines of evidence suggest that the hypothalamic-pituitary-adrenal (HPA) axis may be altered in the syndrome. This review collates evidence to determine the nature of HPA axis baseline activity and reactivity (as measured by glucocorticoid levels) differences in FXS, and its relationship to behaviour. Through a search of electronic databases, 15 papers were identified which provided data on humans with FXS or the FMR1 knockout mouse model. The findings across studies are mixed, though trends in the findings can be seen, including elevations in cortisol levels, particularly in males. Preliminary findings also highlight associations between cortisol levels and key behaviours associated with the syndrome, such as gaze avoidance. Areas for future research are discussed

Complexity on the Periphery: A Study of Regional Organization at Banavasi, c.1st - 18th Century A.D.

This dissertation uses archaeological and historical approaches to discuss the organization of a complex polity that lay in what has been considered a ‘peripheral’ zone in peninsular India, located outside the core areas of larger states and empires. Through a systematic survey of a 50 sq. km area at Banavasi, a regional capital, I analyze the long-term archaeological landscape to discuss changes in socio-religious and political organization as the area cycled into and out of political centrality. I conclude by proposing a tentative model for Banavasi as a nodal point. First, I argue that, although located in a peripheral area, Banavasi can be considered a regional center of some permanence- a ‘peripheral core’. Banavasi’s importance lies in part in its early development as a regional administrative and sacred center. Archaeologically, the sacred landscape of Banavasi reveals several of the complex processes of the legitimation of power, both of intermediate elite groups and of groups higher in the political hierarchy. By the tenth century, this involved a relationship of elite patronage and Brahmanical legitimation that drew on established patterns elsewhere in the subcontinent. Banavasi provided a space where this interaction between political and religious power could be displayed through the construction of Brahmanical temples or the donation of land. Second, Banavasi’s development can be linked to the presence of an intermediate elite family that appropriated the Banavasi area as their ‘core’. Through an analysis of a corpus of early inscriptions, issued by the Kadamba dynasty and dated between the fourth and seventh centuries AD, I consider some of the networks of alliances with larger political entities and with ones on a similar scale that structured the Banavasi area during this period. In this dissertation I have questioned the idea that peripheral regions were necessarily static entities by highlighting the complex nature of inter-regional interaction and the development of socio-political complexity, including the role of intermediate elites, in these areas. I also suggest that in a context of cycling and ephemeral states and empires, smaller but long-lived peripheral areas characterized by small centers and elite families are essential units of historical analysis.PhDAnthropologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97865/1/uthara_1.pd

Fragile X syndrome and the amygdala

Fragile X Syndrome (FXS) is the most commonly inherited form of mental impairment and autism. Current understanding of the molecular and cellular mechanisms underlying FXS symptoms is derived mainly from studies on the hippocampus and cortex. However, FXS is also associated with strong emotional symptoms, which are likely to involve changes in the amygdala. Unfortunately, the synaptic basis of amygdalar dysfunction in FXS remains largely unexplored. Here we describe recent findings from mouse models of FXS that have identified synaptic defects in the basolateral amygdala that are in many respects distinct from those reported earlier in the hippocampus. Long-term potentiation and surface expression of AMPA-receptors are impaired. Further, presynaptic defects are seen at both excitatory and inhibitory synapses. Remarkably, some of these synaptic defects in the amygdala are also amenable to pharmacological rescue. These results also underscore the need to modify the current hippocampus-centric framework to better explain FXS-related synaptic dysfunction in the amygdala

Effects of chronic and acute stress on rat behaviour in the forced-swim test

Stress and depression may share common neural plasticity mechanisms. Importantly, the development and reversal of stress-induced plasticity requires time. These temporal aspects, however, are not captured fully in the Forced-Swim Test (FST), a behavioural model for testing antidepressant efficacy, used originally in naive animals. The present study probed whether and how a rodent model of stress affects behaviour in the FST over time. We found that the intensity and duration of stress are critical in the development of depressive symptoms in male Wistar rats (n = 37) as tested in the FST. Chronic immobilization stress (2 h/day for 10 days) elicited a range of responses, from low to high values of immobility in the FST on day 1 and subsequent immobility on day 2 was inversely related to individual day 1 values. As a whole, chronically stressed rats did not exhibit any significant change in immobility either on day 1 or day 2 compared to control rats. However, climbing behaviour was reduced uniformly from day 1 to day 2, despite the differences in immobility. In contrast, a separate group of rats (n = 30) subjected to the same chronic stressor displayed a significant reduction in open-arm exploration in the elevated plus maze, indicative of a robust increase in anxiety-like behaviour. Furthermore, when the 10-day chronic stress paradigm was reduced to a single 2-h episode of immobilization stress, it triggered a uniform day 1 to day 2 increase in immobility, which was not persistent 10 days later. These results highlight a need for closer examination of the ways in which stress-induced modulation of behaviour in the FST may be used and interpreted in future studies aimed at exploring connections between stress and depression

Stress enhances fear by forming new synapses with greater capacity for long-term potentiation in the amygdala

Prolonged and severe stress leads to cognitive deficits, but facilitates emotional behaviour. Little is known about the synaptic basis for this contrast. Here, we report that in rats subjected to chronic immobilization stress, long-term potentiation (LTP) and NMDA receptor (NMDAR)-mediated synaptic responses are enhanced in principal neurons of the lateral amygdala, a brain area involved in fear memory formation. This is accompanied by electrophysiological and morphological changes consistent with the formation of ‘silent synapses’, containing only NMDARs. In parallel, chronic stress also reduces synaptic inhibition. Together, these synaptic changes would enable amygdalar neurons to undergo further experience-dependent modifications, leading to stronger fear memories. Consistent with this prediction, stressed animals exhibit enhanced conditioned fear. Hence, stress may leave its mark in the amygdala by generating new synapses with greater capacity for plasticity, thereby creating an ideal neuronal substrate for affective disorders. These findings also highlight the unique features of stress-induced plasticity in the amygdala that are strikingly different from the stress-induced impairment of structure and function in the hippocampus