(5) fear signaling

Every animal with a well-developed central nervous system—from snails to mice to monkeys to people—can become afraid, or anxious…Anxiety—fear itself—is a universal, instinctive response to a threat to one’s body or social status and is therefore critical for survival…William James proposed that the cognitive experience of emotion is secondary to the physiological expression of emotion….”We feel sorry because we cry, angry because we strike, afraid because we tremble”…Objectively distinguishable emotions are correlated with specific patterns of autonomic, endocrine, and voluntary responses. Furthermore, people whose spinal cord has been accidentally severed, cutting off feedback from the autonomic nervous system in regions of the body below the injury, appear to experience less intense emotions….

Yet feelings can be sustained long after a threat has subsided. Conversely, some feelings arise much more rapidly than changes in the body…Antonio Damasio argues that the experience of emotion is essentially a higher order representation of the bodily reactions and that this representation can be stable and persistent…A consensus is emerging on how emotions are generated. The first step is thought to be the unconscious, implicit evaluation of a stimulus, followed by physiological responses, and finally by conscious experience that may or may not persist…

The unconscious component of emotion involves the operation of the ANS and the hypothalamus, which regulates it. The conscious component of emotion involves the evaluative functions of the cerebral cortex, which are carried out by the cingulated cortex. Central to both components is the amygdala, thought to coordinate the conscious experience of feeling and the bodily expression of emotion, particularly fear…Damage to the amygdala, disrupts the ability of an emotionally charged stimulus to elicit an emotional response. In contrast, damage to the hippocampus interferes with the ability to remember the context in which the stimulus occurred…Joseph LeDoux and Michael Davis delineated how information from conditioned and unconditioned stimuli reaches the amygdala and how the amygdala initiates a fear response…The sensory neurons send their axons to a cluster of neurons in the thalamus…that form two pathways: a direct pathway that goes straight to the lateral nucleus of the amygdale without ever contacting the cortex, and an indirect pathway that goes first to the auditory cortex and then to the lateral nucleus.

I studied slices of the mouse amygdala. Earlier studies had shown that both the direct and indirect pathways are strengthened through a variant of long-term potentiation…We found that it has a molecular signaling pathway that includes cAMP, protein kinase A, and the regulatory gene CREB…WE found that the pyramidal cells express a gene that encodes a peptide neurotransmitter called gastrin-releasing peptide. We next found that the target cells are a special population of inhibitory interneurons that contain receptors for gastrin-releasing peptide. The target cells then connect back to the pyramidal cells. The circuit we traced is called a negative feedback circuit…We tested a genetically modified mouse whose receptors for gastrin-releasing peptide had been deleted, thus interrupting the inhibitory feedback circuit…We found dramatically enhanced long-term potentiation in the lateral nucleus and a significantly enhanced and persistent memory of fear. The effect proved to be remarkably specific to learned fear: the same mutant mice showed normal innate fear on a variety of other tests.

When we looked in the lateral nucleus of mice that had undergone safety training, we found the opposite of long-term potentiation: namely, a long-term depression in the neural response to the tone…We found that the response ni the striatum is dramatically enhanced, consisten with the positive sensation of feeling safe.

We engineered mice with a gene that expresses a superabundance of D2 receptors in the striatum, as is found in schizophrenics. We found that such mice do indeed have deficits in working memory…Once a mouse reached adulthood, we turned off the transgene responsible for the production of excessive dopamine receptors and found that the defect in working memory was unabated. In other words, correcting the molecular defect in adult brains did not correct the cognitive defect. This result suggest that an overabundance of D2 receptors during development causes changes in the mouse brain that persist into adulthood…We have now tracked down at least one change that occurs in the PFC as a result of the overproduction of D2 receptors: a decrease in the activation of another dopamine receptor: the D1 receptor…Decreasing D1 receptor activation also decreases cAMP, causing a deficiency in working memory.

Monoamine oxidase inhibitor (MAOI) was initially developed to fight a very different disorder, tuberculosis…Physicians soon notice dthat patients receiving these MAOIs were amazingly upbeat…The most effective antidepressant drugs are known as selective serotonin reuptake inhibitors…Antidepressant drugs also increase the ability of a small region of the hippocampus, the dentate gyrus, to generate new nerve cells…Hen used radiation to destroy the dentate gyrus in a mouse model of depression caused by stress. He found that anti-depressants could no longer reverse depression like behavior in mice.

We showed volunteers pictures of faces with fearful expressions, we found prominent activity in the amygdala. Unconscious perception of fearful faces activated the basolateral nucleus…in direct proportion to a person’s background anxiety…Conscious perception of fearful faces, in contrast, activated the dorsal region of the amygdala, which contains the central nucleus, and it did so regardless of a person’s background anxiety. (p.339-351)