Longitudinal microstructural changes in 18 amygdala nuclei resonate with cortical circuits and phenomics.

The amygdala nuclei modulate distributed neural circuits that most likely evolved to respond to environmental threats and opportunities. So far, the specific role of unique amygdala nuclei in the context processing of salient environmental cues lacks adequate characterization across neural systems and over time. Here, we present amygdala nuclei morphometry and behavioral findings from longitudinal population data (>1400 subjects, age range 40-69 years, sampled 2-3 years apart): the UK Biobank offers exceptionally rich phenotyping along with brain morphology scans. This allows us to quantify how 18 microanatomical amygdala subregions undergo plastic changes in tandem with coupled neural systems and delineating their associated phenome-wide profiles. In the context of population change, the basal, lateral, accessory basal, and paralaminar nuclei change in lockstep with the prefrontal cortex, a region that subserves planning and decision-making. The central, medial and cortical nuclei are structurally coupled with the insular and anterior-cingulate nodes of the salience network, in addition to the MT/V5, basal ganglia, and putamen, areas proposed to represent internal bodily states and mediate attention to environmental cues. The central nucleus and anterior amygdaloid area are longitudinally tied with the inferior parietal lobule, known for a role in bodily awareness and social attention. These population-level amygdala-brain plasticity regimes in turn are linked with unique collections of phenotypes, ranging from social status and employment to sleep habits and risk taking. The obtained structural plasticity findings motivate hypotheses about the specific functions of distinct amygdala nuclei in humans.

4E-BP2-dependent translation in cerebellar Purkinje cells controls spatial memory but not autism-like behaviors.

Recent studies have demonstrated that selective activation of mammalian target of rapamycin complex 1 (mTORC1) in the cerebellum by deletion of the mTORC1 upstream repressors TSC1 or phosphatase and tensin homolog (PTEN) in Purkinje cells (PCs) causes autism-like features and cognitive deficits. However, the molecular mechanisms by which overactivated mTORC1 in the cerebellum engenders these behaviors remain unknown. The eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) is a central translational repressor downstream of mTORC1. Here, we show that mice with selective ablation of 4E-BP2 in PCs display a reduced number of PCs, increased regularity of PC action potential firing, and deficits in motor learning. Surprisingly, although spatial memory is impaired in these mice, they exhibit normal social interaction and show no deficits in repetitive behavior. Our data suggest that, downstream of mTORC1/4E-BP2, there are distinct cerebellar mechanisms independently controlling social behavior and memory formation.

Beyond STDP-towards diverse and functionally relevant plasticity rules.

Synaptic plasticity, induced by the close temporal association of two neural signals, supports associative forms of learning. However, the millisecond timescales for association often do not match the much longer delays for behaviorally relevant signals that supervise learning. In particular, information about the behavioral outcome of neural activity can be delayed, leading to a problem of temporal credit assignment. Recent studies suggest that synaptic plasticity can have temporal rules that not only accommodate the delays relevant to the circuit, but also be precisely tuned to the behavior the circuit supports. These discoveries highlight the diversity of plasticity rules, whose temporal requirements may depend on circuit delays and the contingencies of behavior.

Depressed by Learning-Heterogeneity of the Plasticity Rules at Parallel Fiber Synapses onto Purkinje Cells.

Climbing fiber-driven long-term depression (LTD) of parallel fiber synapses onto cerebellar Purkinje cells has long been investigated as a putative mechanism of motor learning. We recently discovered that the rules governing the induction of LTD at these synapses vary across different regions of the cerebellum. Here, we discuss the design of LTD induction protocols in light of this heterogeneity in plasticity rules. The analytical advantages of the cerebellum provide an opportunity to develop a deeper understanding of how the specific plasticity rules at synapses support the implementation of learning.

Timing Rules for Synaptic Plasticity Matched to Behavioral Function.

It is widely assumed that the complexity of neural circuits enables them to implement diverse learning tasks using just a few generic forms of synaptic plasticity. In contrast, we report that synaptic plasticity can itself be precisely tuned to the requirements of a learning task. We found that the rules for induction of long-term and single-trial plasticity at parallel fiber-to-Purkinje cell synapses vary across cerebellar regions. In the flocculus, associative plasticity in vitro and in vivo is narrowly tuned for an interval of ∼120 ms, which compensates for the specific processing delay for error signals to reach the flocculus during oculomotor learning. In the vermis, which supports a range of behavioral functions, plasticity is induced by a range of intervals, with individual cells tuned for different intervals. Thus, plasticity at a single, anatomically defined type of synapse can have properties that vary in a way that is precisely matched to function.

Neighborhood matters: divergent patterns of stress-induced plasticity across the brain.

The fact that exposure to severe stress leads to the development of psychiatric disorders serves as the basic rationale for animal models of stress disorders. Clinical and neuroimaging studies have shown that three brain areas involved in learning and memory--the hippocampus, amygdala and prefrontal cortex--undergo distinct structural and functional changes in individuals with stress disorders. These findings from patient studies pose several challenges for animal models of stress disorders. For instance, why does stress impair cognitive function, yet enhance fear and anxiety? Can the same stressful experience elicit contrasting patterns of plasticity in the hippocampus, amygdala and prefrontal cortex? How does even a brief exposure to traumatic stress lead to long-lasting behavioral abnormalities? Thus, animal models of stress disorders must not only capture the unique spatio-temporal features of structural and functional alterations in these brain areas, but must also provide insights into the underlying neuronal plasticity mechanisms. This Review will address some of these key questions by describing findings from animal models on how stress-induced plasticity varies across different brain regions and thereby gives rise to the debilitating emotional and cognitive symptoms of stress-related psychiatric disorders.

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.

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 naïve 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.

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS), a common inherited form of mental impairment and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. Earlier studies have identified a role for aberrant synaptic plasticity mediated by the metabotropic glutamate receptors (mGluRs) in FXS. However, many of these observations are derived primarily from studies in the hippocampus. The strong emotional symptoms of FXS, on the other hand, are likely to involve the amygdala. Unfortunately, little is known about how exactly FXS affects synaptic function in the amygdala. Here, using whole-cell recordings in brain slices from adult Fmr1 knockout mice, we find mGluR-dependent long-term potentiation to be impaired at thalamic inputs to principal neurons in the lateral amygdala. Consistent with this long-term potentiation deficit, surface expression of the AMPA receptor subunit, GluR1, is reduced in the lateral amygdala of knockout mice. In addition to these postsynaptic deficits, lower presynaptic release was manifested by a decrease in the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), increased paired-pulse ratio, and slower use-dependent block of NMDA receptor currents. Strikingly, pharmacological inactivation of mGluR5 with 2-methyl-6-phenylethynyl-pyridine (MPEP) fails to rescue either the deficit in long-term potentiation or surface GluR1. However, the same acute MPEP treatment reverses the decrease in mEPSC frequency, a finding of potential therapeutic relevance. Therefore, our results suggest that synaptic defects in the amygdala of knockout mice are still amenable to pharmacological interventions against mGluR5, albeit in a manner not envisioned in the original hippocampal framework.