a) Inhibitory synaptic transmission in amygdala? Fear behaviors, which serve to protect the organism from dangers, can become maladaptive during mental illness. As amygdala is responsible for control of fear behaviors, we are trying to understand how its synaptic properties relate to its fear-regulating functions. To analyze this relationship we perform parallel behavioral and physiological studies. In the behavioral experiments we employ auditory fear conditioning as a simple model of fear learning. In the physiological studies, we analyze synaptic properties of the sensory inputs to amygdala, which are believed to be responsible for the auditory fear conditioning. In previous years we discovered that mice with the forebrain-restricted knockout of a small GTPase Rap1 are impaired in fear learning and have reduced anxiety. Using whole-cell recording, we also found that this mutation selectively enhanced synaptic transmission in the cortical, but not in the thalamic input to lateral amygdala. These findings resulted in a question as how enhancement of synaptic transmission in amygdala inputs could suppress amygdala function. ? During the last fiscal year we were trying to address this question by exploring mechanisms of amygdala inhibition. We compared how stimulation of amygdala afferents affects synaptic transmission in glutamatergic inputs to excitatory and to inhibitory neurons and found that the inputs to amygdala interneurons were potentiated much easier than the input to principle neurons. Furthermore, during such stimulation, the inputs to principle neurons were strongly inhibited via presynaptic GABAb-receptor, whereas inputs to interneurons were not. The mechanism responsible for this preferential recruitment of GABAb receptors on inputs to principle neurons was differential release of extrasynaptic GABA in the vicinity of principle neurons and interneurons. ? With these findings we revealed a novel mechanism that underlies inhibitory dominance inside amygdala. Our future plan is to investigate whether this mechanism becomes impaired during conditions that resemble pathological states of fear. ? ? b) Modeling emotional behaviors specific to the period of adolescent development? In previous years we discovered that in mice synaptic transmission in the amygdala inputs undergoes late developmental changes (loss of synaptic plasticity and increase in the efficacy of synaptic transmission in the thalamic input to amygdala), which occur between postnatal day 35 and postnatal day 56, the time corresponding to adolescence in humans. Adolescence is considered a critical period for emotional development. It is characterized by enhanced emotional responses and risk-taking behaviors. Yet, animal models of adolescent emotionality have not been established and neuronal substrates underlying this phenomenon have not been found. ? Following our earlier finding of dramatic changes taking place in the thalamic, but not in the cortical input to amygdala during adolescence, during the last fiscal year, we were trying to identify a rodent behavioral paradigm which would model heightened adolescent emotionality and which could be linked to amygdala functions. To this end we compared behaviors of adult and late juvenile mice in variants of a Pavlovian fear conditioning. We discovered that juvenile mice had higher levels of generalization of auditory fear conditioning than their adult counterparts. This generalization was not caused by non-associative sensitization to aversive stimulation, neither was it related to the perception of the novelty component of conditional stimulus. Furthermore, this form of fear generalization to an auditory stimulus was abolished by explicitly unpaired presentation of this stimulus with the aversive unconditional stimulus, indicating that despite higher fear generalization adolescents possess mechanisms to avoid non-adaptive fear. Given the developmental coincidence between the physiological changes in the properties of the thalamo-amygdala input and behavioral changes in fear generalization, out future work is focused on a question as whether enhanced plasticity in the thalamic input to amygdala is the synaptic mechanism that can account for the increased fear generalization in juvenile mice.
| Ito, Wataru; Pan, Bing-Xing; Yang, Chao et al. (2009) Enhanced generalization of auditory conditioned fear in juvenile mice. Learn Mem 16:187-92 |
| Pan, Bing-Xing; Vautier, Francois; Ito, Wataru et al. (2008) Enhanced cortico-amygdala efficacy and suppressed fear in absence of Rap1. J Neurosci 28:2089-98 |
