Fear-induced skeletal motor activation
'Fight or flight' responses
Facial expression of fear
Paraventricular nucleus of the '-----
Fear-induced parasympathetic nervous system activation
Fear-induced ->» sympathetic nervous -system activation
Fear-induced neuroendocrine and neuropeptide release
Increased urination • Defecation Ulcers Bradycardia
Tachycardia increased blood pressure sweating Piloerection pupil Dilatation
'Hormonal stress response'
Figure 1 Key anatomical pathways comprising the 'fear neurocircuitry' underlying fear- and anxiety-induced responses. This circuitry centers on the amygdala and includes afferent input from sensory cortex and thalamus in response to external threat, activation of numerous reciprocal connections to the amygdala that are involved in processing this afferent information and incorporating information from memory stores, and the efferent systems ultimately responsible for eliciting the physiological and behavioral responses characteristic of fear and anxiety states. (Reproduced with permission from Charney, D. S.; Deutch, A. Orit. Rev. Neurobiol. 1996, 10, 419-446.)
anterior cingulate, and medial and orbitofrontal cortex, is involved in attenuating fear responses and extinguishing behavioral responses to fear-conditioned stimuli that are no longer reinforced. In this way, the mFC ameliorates the fear response when the threat has been removed or its import altered. In addition, the flow of information reaching the AMYG is regulated at the level of the thalamus, via cortico-striato-thalamic projections.
The AMYG has considerable reciprocal connections with the bed nucleus of the stria terminalis (BNST) that is proposed to be part of an 'extended amygdala,' based on its chemoarchitecture and parallel neurocircuitry. The BNST, as well as the CeA, project to the hypothalamus and other brainstem nuclei that play a role in regulation of the autonomic and neuroendocrine aspects of fear and anxiety. Stimulation of the lateral hypothalamus via direct projections from the CeA, as well as through projections via the locus coeruleus, results in activation of the sympathetic nervous system and leads to increases in blood pressure, heart rate, sweating, piloerection, and pupil dilation, whereas projections to the dorsal motor nucleus of the vagus are involved in activation of the parasympathetic nervous system and lead to increases in urination, defecation, and decreased heart rate. Similarly, projections from the CeA to the parabrachial nucleus are involved in activation of respiration, or fear-induced hyperventilation. Projections from the CeA and the locus coeruleus to the paraventricular nucleus of the hypothalamus are important in regulating the hypothalamic-pituitary-adrenal (HPA) axis response to stressful or fearful stimuli.
The behavioral components of fear responding are also coordinated to a large extent by the AMYG. Direct projections from the CeA to the ventral lateral periaqueductal gray (PAG) are thought to mediate freezing behavior in response to threatening stimuli.14 In contrast, efferent projections from the CeA to lateral PAG, as well as from the basal nucleus to the nucleus accumbens and striatum are thought to mediate active avoidance behaviors to fear. It is a complex interaction of pathways that are involved in eliciting motor responses to threat, including activation of the musculoskeletal system for 'fight or flight.' These include cortical association areas and motor cortex and multiple areas within the striatum, including the nucleus accumbens, the olfactory tubercle and parts of the caudate and putamen. The AMYG densely innervates both the prefrontal cortex and the striatum and is positioned to play a role in the regulation of both of these systems in response to threatening stimuli.
While the neuroanatomical correlates underlying fear and anxiety are quite complex, the brain areas described above are thought to be key components of this neurocircuitry and provide a basis for the exploration into the human neurocircuitry underlying specific anxiety disorders.
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