Parent-Child Autonomic Synchrony During Vicarious Extinction Learning in Pediatric PTSD

Children must learn basic functional processes directly from their caregivers and child psychopathology may disrupt this transmission. This transmission may be seen through biological measures like peripheral nervous system outputs like skin conductance (SCR). Fear learning deficits have been seen in affective disorders like PTSD and are useful for studying parent-child learning transmission. Our study uses a vicarious fear extinction paradigm to study if biological synchrony (SCR and heart rate variability (HRV)) are potential mechanisms in which children learn safety cues from their parents. There were 16 dyads (PTSD n=11, TD n=5) undergoing a vicarious fear extinction paradigm. We used cross-recurrence quantification analysis (CRQA) to assess SCR and HRV synchrony between parent-child dyads. We then used a linear model looking at group differences between PTSD dyads and typically developing (TD) dyads. For SCR, we saw a significant group difference (p=.037) indicating that TD dyads had higher SCR synchrony compared to PTSD dyads. For HRV, there were no group differences between PTSD and TD dyads (p=.325). These results suggest that SCR synchrony, but not HRV, may be a potential mechanism that allows for fear and safety learning in youth. While this is preliminary, it may give the first insights on how therapies such as Trauma-Focused Cognitive Behavioral Therapy critically rely on parental coaching to model appropriate fear responses to help their child to recover from trauma.

Localized Synaptic Potentiation is Necessary and Sufficient for Context Fear Memory

The nature and distribution of the synaptic changes that underlie memory are not well understood. We examined the synaptic plasticity behind context fear learning and found that conditioning produced potentiation of excitatory synapses specifically onto the basolateral amygdala neurons activated during learning. This synaptic potentiation lasted at least 7 days, and its disruption impaired memory recall. High frequency optogenetic stimulation of the CS and US-activated ensembles or biochemical induction of synaptic potentiation in US-responsive neurons alone was sufficient to produce a context fear association without prior associative training. These results suggest that plasticity of CS inputs onto US-responsive amygdala neurons is a necessary and sufficient step in forming context fear associations, and that context discrimination is determined by the CS-specific amygdala inputs activated during retrieval.

A striatal circuit balances learned fear in the presence and absence of sensory cues

During fear learning, defensive behaviors need to be finely balanced, to allow animals to return to normal behaviors after the termination of threat-indicating sensory cues. Nevertheless, the circuits underlying such balancing are largely unknown. Here, we investigate the role of direct (D1R+) - and indirect (Adora+) pathway neurons of the amygdala-striatal transition zone (AStria) in fear learning. In-vivo Ca2+ imaging revealed that fear learning increased the responses of D1R+ AStria neurons to an auditory CS, given that the animal moved. In Adora+ neurons, fear learning also induced a differential activity during freezing and movement, albeit with little influence of the CS. In-vivo optogenetic silencing during the training day showed that plasticity in D1R+ AStria neurons contributes to auditory-cued fear memories, whereas Adora+ neurons suppressed learned freezing when no CS was present. Circuit tracing experiments identified cortical input structures to the AStria, and recording of optogenetically-evoked EPSCs at the corresponding projection revealed different forms of long-term plasticity at synapses onto D1R+ and Adora+ AStria neurons. Taken together, direct- and indirect pathways neurons of the AStria show differential signs of in-vivo and ex-vivo plasticity after fear learning, and balance defensive behaviors in the presence and absence of aversively motivated sensory cues.

Dopamine and fear memory formation in the human amygdala

Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

Regional gray matter oligodendrocyte- and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans

Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter oligodendrocytes contribute to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin basic protein (MBP) content in multiple brain areas. We found that oligodendrocyte cell density and MBP were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and MBP. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with MBP in the amygdala and spatial-processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species-independent relationship between region-specific, gray matter oligodendrocytes and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.