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Title: Pivotal role of GABAergic neurons of the basolateral amygdala in relaying hippocampal and serotonergic information
Author: Bocchio, Marco
ISNI:       0000 0004 6497 3645
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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The amygdala is a brain structure located in the temporal lobe that coordinates a wide range of emotional behaviours, in particular fear responses. Neuroimaging studies in humans have shown that in patients with post-traumatic stress disorder (PTSD) and phobias the amygdala is hyper-responsive to emotional stimuli. Thus, deciphering the neuronal mechanisms through which the amygdala orchestrates fear responses may improve treatments for pathological fear. In the last decades it has become evident from rodent experiments that neuronal circuits of the basolateral nucleus of the amygdala (BLA) control the acquisition and retrieval of fear memories. This is achieved through precise control of glutamatergic principal neuron (PN) activity by the release of ?-aminobutyric acid (GABA) from distinct populations of inhibitory neurons. Notably, the firing of BLA neurons is moulded by a vast array of extrinsic structures, namely sensory areas of the cortex, regions involved in memory processing and subcortical neuromodulatory afferents. However, the cellular mechanisms enabling the modulation of BLA circuits by afferent regions are still poorly understood. The modulation of BLA circuits by the hippocampus and by the neuromodulator serotonin (5-HT) is of particular interest because these pathways may be of clinical importance. Nonetheless, these inputs have received little attention using circuit-based approaches. To fill this gap, I used a combination of ex vivo recordings from brain slices, in vivo recordings from anaesthetised mice, optogenetics, pharmacology, behavioural tests and immunohistochemistry. These experiments reveal that GABAergic neurons of the BLA are key nodes through which hippocampus and 5-HT modulate the excitability of PNs, the main output of the BLA. Specifically, optogenetic activation of ventral hippocampus pyramidal cells axons recruits BLA GABAergic interneurons that provide feedforward inhibition onto PNs. However, activation of hippocampal axons at theta frequency triggers a GABAB dependent depression of feedforward inhibition, creating time windows in which the induction of synaptic plasticity of parallel excitatory pathways is facilitated. Furthermore, GABAergic interneurons expressing parvalbumin (PV) are a prominent target of the 5-HT action in the BLA. 5-HT depolarizes these cells via 5-HT2A receptors, enhancing PN inhibition. Remarkably, in mice overexpressing the 5-HT transporter (5-HTT), an animal model of a genetic 5-HTT variation occurring in humans, PV+ interneurons display reduced depolarization by 5-HT and diminished recruitment by fear memory recall. Finally, I report a novel GABAergic neuron type of the BLA that expresses high levels of neuronal nitric oxide synthase (nNOS). These cells are instead hyperpolarized by 5-HT via 5-HT1A receptors, representing the first example of a BLA inhibitory neuron inhibited by this neuromodulator. Assessment of their c-Fos immunoreactivity showed that nNOS+ cells are active during sleep but not during wakefulness. Since 5-HT is highly released during the latter but not the former vigilance state, its hyperpolarizing action on nNOS+ cells provides a putative mechanism through which these cells are activated in a brain state-dependent fashion. My results demonstrate that hippocampus and 5-HT influence BLA microcircuits via prominent action on GABAergic cells. Notably, 5-HT appears to exert GABAergic cell type specific actions, suggesting that studying the impact of extrinsic pathways on defined amygdala neuron types can be decisive to comprehend the neural circuits controlling emotional learning.
Supervisor: Capogna, Marco Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available