Neurobiology of fear and anxiety

Fear is an emotional response when faced with a threatening situation. When fear is significantly more than it should be called fear; when there is no real threat, fear or fear is called anxiety. In the past used to think the mood is difficult to discuss with neuroscience methods, but now the mood has become a hot research topic in neuroscience. Great progress has been made in the study of neural pathways and mechanisms of fear and anxiety. This type of research is based on classical conditioning, using new research methods, such as micro-coagulation and micro-drug injections, causing limited damage to a particular neural structure, and then observing its associated behavioral effects, or The method of recording electrical physiology neurophysiological changes.

First, classic fear conditioning

This is the easiest and most direct way to study fear. People will have defensive reactions in the face of fear, including: (1) behavior changes, will choose to fight or escape; (2) changes in autonomic function, rapid heartbeat, elevated blood pressure and sweating; (3) neuroendocrine changes Mainly the hypothalamic-pituitary-adrenal (hPA) axis activity is enhanced and blood cortisol levels are elevated. A similar reaction can also be induced by conditioned reflection. Neutral stimuli, such as monotonous sounds (conditional stimuli), are given to the test animal simultaneously with a fear-inducing stimulus (such as an electric shock to the foot). After repeated several times, the conditional stimuli can also cause similar fear in the test animal. Behavior, autonomic and neuroendocrine responses. These reactions are directly caused by fear, not learned or conditional reflexes. In other words, fear conditioning is not related to the acquisition of the reaction, but the new stimulus is linked to the original response [1]. Fear conditioning is seen in a variety of organisms, and the horological reflex mechanisms of vertebrates are very similar. Evidence suggests that the amygdala and its projection may be central control systems that mediate the expression and acquisition of conditional reflex fear [1].

Second, listen to scare reflection

(1) Enhancement of listening to scare reflection

1. fear-potentiated startle effect: Suddenly stimulating a subject with a loud sound can cause a frightening reflex. The intensity of the reflection can be obtained using physiological indicators such as blinking (eyeb Link )measuring. When this reflection is combined with conditioning, the intensity of the listening and frightening reflection can be enhanced. For example, 3 to 4 s after the light is turned on, the subject animal is given a sound stimulus, causing a frightening reflection of general intensity. When the light is given to the test subject in pairs with the electric shock foot, after several stimulations, the sound is stimulated 3 to 4 s after the same light is turned on, and the intensity of the scare reflection is significantly increased. If only the light is given, and the foot is not shocked, after a few times, the intensity of the shocking reflection caused by the sound alone returns to its original level. Brown et al. (1951) first described the fear-enhancing startle effect. Falls et al. [2] believed that after the pairing of the light and the electric shock to the foot, the light caused a state of fear that enhanced the intensity of the reflection. Anti-anxiety drugs such as diazepam or buspirone not only reduce the fear response, but also reduce the startle effect caused by the light. Davis et al [3] believe that the increase in the startle response caused by lighting and electric shock is a stimulus-specific fear.

2. Light-enhanced startle effect: The sound stimulation is given 5~20 s after the glare is turned on, and the intensity of the shocking reflection is also increased, which is called the light-enhanced startle effect. This effect can be attenuated by pre-administration of buspirone or chlordiazepoxide. It is indicated that the enhancement of scare reflex is an anxiety or sensitive state caused by unconditioned reflex [4]. There are species differences in this effect, such as nocturnal animals (such as rats) are more afraid of light than daytime animals. People are scared of reflexes in the dark, such as many people feel more anxious when they suddenly turn off the lights, especially those who are afraid of darkness when they are young. The shocking reflexes in patients with post-traumatic stress disorder are also significantly enhanced.

3. Corticotropin-releasing hormone (CRH) enhances the startle effect: intraventricular administration of CRH can cause behavioral and neuroendocrine effects similar to fear and anxiety; whereas administration of CRH antagonist α-helix CRH9-41 It can block the behavior and neuroendocrine effects caused by stressors or conditional fear [3]. Swerdlow et al [5] reported that the auditory startle reflex enhanced by intracerebroventricular CRH can be blocked by chlordiazepoxide. It is suggested that the effect of CRH on scare reflex is the anxiety effect caused by this polypeptide hormone, which is another example of the effect of unconditional anxiety.

(2) Listening to the neural pathway of frightening reflex

The frightening reflex is an unconditioned reflex. According to the measurement of the gastrocnemius electromyogram, the latency of listening to the frightening reflex is 8 ms. This suggests that it is a reflection mediated by a simple neural pathway. Davis et al [6] originally believed that there are four sets of synapses in the neural pathway that mediate the shocking and reflexive reflex: the ventral nucleus of the cochlear nerve, the ventromedial region of the ventral nucleus of the lateral thalamic, the reticular nucleus of the caudal cerebral ventricle, and the facial motor Or motor neurons in the anterior horn of the spinal cord. Subsequent studies have shown that there is no synapse in the ventral medial region of the ventral nucleus of the lateral humerus that listens to the scary neural pathway. The evidences are as follows: (1) N-methyl-D-aspartate (nMDA) is used to damage the reticular nucleus of the caudal cerebral ventricle, which can completely eliminate the shocking reflexes; Damage to the lateral nucleus of the lateral ventral nucleus or the ventral medial area does not disappear [7]. (2) Injecting the NMDA receptor antagonist DL-2-amino-5-phosphate valeric acid into the ventral region of the lateral collateral to reduce the startle response, and injecting 1/60 of the above dose into the reticular nucleus of the pons Can reduce the scare reflection by 80% to 90% [8]. (3) Injection of a small dose of non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline into the reticular nucleus of the caudal cerebral ventricle also reduces the shocking response, and the injection into the ventral aspect of the lateral humerus is ineffective [ 9]. Therefore, the pathway to listen to scare reflexes consists of tertiary neurons: cochlear root neurons, cerebral nucleus nucleus neurons and motor nucleus or motor neurons in the anterior horn of the spinal cord.

Third, the neural pathway of fear conditioning

Conditional reflexes contain learned components and are involved in advanced neurological centers. Different stimuli, such as hearing, visual and olfactory stimuli, can be used as conditional stimuli. As mentioned above, the auditory stimulation passes along the auditory nerve to the root nucleus of the cochlea, and reaches the thalamic nucleus in the medial geniculate body via the lateral collateral (the information causing the shock reflex needs to be transmitted to the reticular nucleus of the caudal cerebral ventricle), and then transmitted to the nucleus of the thalamus. Two different target areas - the amygdala and the auditory cortex, and the information that reaches the auditory cortex are finally projected onto the amygdala. It is speculated that the information provided by the thalamic nucleus to the amygdala is rapid but inaccurate; while the information provided by the auditory cortex to the amygdala is slightly delayed, but more accurate. Therefore, the amygdala is a key part of fear information processing and fear acquisition [1].

Fourth, the amygdala circuit [1]

Anatomical and physiological studies suggest that the lateral nucleus of amygdala (LA) is the main site of the afferent passage of the thalamus and cortex. In fact, every neuron in LA receives convergent afferents from the auditory brain and cortex. In addition, the central nucleus of amygdala (CEA) appears to be in close contact with the motor system that controls the conditioned reflex response, ie CEA controls the expression of defense responses, including behavioral responses, autonomic responses, and HPA axis responses. Damage to the lateral hypothalamus affects sympathetic nervous system activity (such as changes in blood pressure), and damage to central gray matter affects conditional behavioral responses (such as stiffness).

Information from LA to CEA is through the inner loop of the amygdala. The incoming information arriving at LA is assigned to the basal nucleus (B), the accessory basal nucleus (AB), and CEA, and a small portion to several other regions. The incoming B and AB are projected to CEA. Impairing LA and CEA (without damaging other nuclei) can block fear conditioning of tonal stimuli, suggesting that direct projection from LA to CEA is sufficient to mediate conditioned reflexes.

The research on the inner loop of the amygdala is still deep. Anatomical and physiological studies suggest that the hearing information is primarily received by the dorsal subnucleus of LA; the medial subnucleus receives information from the dorsal subnucleus and signals the majority of the amygdala in LA. A similar situation exists in other nuclei of the amygdala. Therefore, if you want to understand how the amygdala handles information, you need to study at the subnuclear level.

5. The different roles of the central and nuclear nucleus of the almond in fear and anxiety [3]

CEA and the bed nucleus of stria terminalis (BST) have very similar afferent and efferent connections: they receive processed sensory information from the basolateral nucleus of the amygdala, all projected to participate in mediating fear and anxiety. Specific symptoms and signs of the hypothalamus and brainstem and other parts. Davis et al. [3] found that these two structures stimulate specific fear (fear-enhancing scare effect), anxiety or sensitive state (light-enhanced startle effect) and polypeptide-induced unconditional anxiety (CRH-enhanced startle effect) There is a clear difference in the role: damage CEA can completely block the stimulation-specific fear, but has no effect on anxiety or sensitive state and unconditional anxiety; damage to BST significantly attenuates anxiety or sensitivity and unconditional anxiety effects, but does not affect Stimulate specific fear. Therefore, BST may be the system responsible for handling anxiety-like signals; CEA is involved in dealing with fear, and perhaps partially involved in anxiety.

In summary, the neural circuits involved in mediating fear include: fear stimulation information is transmitted to the thalamus and corresponding cortex, and then input into LA, which is processed by the internal circuit of the complex amygdala and output by CEA to the relevant nerves of the hypothalamus and brainstem. Nucleus, which regulates the body's physiological and behavioral responses to fear stimuli. Anxiety may have a similar neural circuit. The difference is that BST may be primarily responsible for handling anxiety information, while the amygdala is primarily responsible for handling fear information; another difference may be neurochemical. If you can find the neurochemical differences between the amygdala and BST, people can design new and more effective drugs to treat anxiety and fear.