Luke R. Johnson

In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.

The study of memory in most behavioral paradigms, including emotional memory paradigms, has focused on the feed forward components that underlie Hebb’s first postulate, associative synaptic plasticity. Hebb’s second postulate argues that activated ensembles of neurons reverberate in order to provide temporal coordination of different neural signals, and thereby facilitate coincidence detection. Recent evidence from our groups has suggested that the lateral amygdala (LA) contains recurrent microcircuits and that these may reverberate. Additionally this reverberant activity is precisely timed with latencies that would facilitate coincidence detection between cortical and sub cortical afferents to the LA. Thus, recent data at the microcircuit level in the amygdala provide some physiological evidence in support of the second Hebbian postulate.

Synaptic changes at sensory inputs to the dorsal nucleus of the lateral amygdala (LAd) play a key role in the acquisition and storage of associative fear memory. However, neither the temporal nor spatial architecture of the LAd network response to sensory signals is understood. We developed a method for the elucidation of network behavior. Using this approach, temporally patterned polysynaptic recurrent network responses were found in LAd (intra-LA), both in vitro and in vivo, in response to activation of thalamic sensory afferents. Potentiation of thalamic afferents resulted in a depression of intra-LA synaptic activity, indicating a homeostatic response to changes in synaptic strength within the LAd network. Additionally, the latencies of thalamic afferent triggered recurrent network activity within the LAd overlap with known later occurring cortical afferent latencies. Thus, this recurrent network may facilitate temporal coincidence of sensory afferents within LAd during associative learning.