Variegated Outputs: Efferents from Amygdala

In addition to providing reciprocal projections to many of the sensory regions from which it receives input, the amygdala also sends efferent projections to regions responsible for behavioral, autonomic, and endocrine responses to stress. These outputs are organized in a point-to-point manner. It also provides parallel outputs to multifunctional systems, and there are also parallel outputs from various amygdaloid nuclei to the same functional system.

These anatomical relationships allow amygdala activity to influence the unconditional response to stress and also to provide substrates by which stimuli predictive of impending stressors can produce anticipatory behavioral adjustments.

Hypothalamus. Physical stress produces a variety of neuroendocrine responses, including increases in plasma adreno-corticotropin (ACTH), corticosterone, norepinephrine, and epinephrine. Control of these responses is mediated in part by a direct action of the hypothalamic paraventricular nucleus on pituitary secretion.

The paraventricular hypothalamus has been shown to receive direct projections from the CeA, providing a pathway by which amygdala activity can contribute to endocrine stress responses. Avariety of studies have demonstrated a role for the amygdala in the expression of neuroendocrine responses to stress. Lesions of the amygdala attenuate the elevation of plasma epinephrine, norepinephrine, and corticosterone normally observed following footshock, and similarly attenuate the elevation of plasma ACTH produced by immobilization stress but do not completely block these responses.

However, given that amygdala lesions do not completely block or alter baseline hormone levels, it is possible that the amygdala lesion- induced attenuation of hormone responses reflects disruption of feedforward amygdala-dependent conditional responses rather than an amygdala control of unconditional endocrine responses.

Projections from the LA and the BLA to the hypothalamus are light and target the lateral hypothalamic area. However, the CeA provides substantial inputs to a larger number of hypothalamic nuclei. Most of the projections originate in the medial division.

Moderate to heavy projections are directed to the medial and lateral preoptic area, lateral hypothalamus, and paraventricular nucleus. Lesions of both the CeA of the amygdala and the lateral hypothalamus block the increase in arterial blood pressure caused by a conditional fear stimulus, leading to the suggestion that projections from the amygdala to the lateral hypothalamus mediate this response.

Importantly, the hypertension to the shock unconditional response remains intact following hypothalamic lesions. In addition to these direct projections to the hypothalamus, the CeA has strong projections to the bed nuclei of the stria terminalis, which also innervates hypothalamic nuclei. Thus, the lateral hypothalamus seems to mediate conditional sympathetic autonomic arousal to fear stimuli via input from the CeA.

Periaqueductal Gray. The CeA projects heavily to the caudal half of the midbrain PAG. These projections initially innervate more dorsal regions of the PAG, areas that serve active or circa strike defensive behaviors and autonomic arousal. Stimulation of the medial and central amygdala inhibits the behaviors that are generated by stimulation of these dorsal regions of the PAG.

As one moves caudally in the PAG, the CeA projections gradually rotate to innervate the ventral portions of the PAG. These ventral PAG areas are essential for conditional fear-related defenses such as freezing. This area is also critical for the opioid analgesia that accompanies fear. Consistent with this pattern, cells in the caudal ventral PAG express c-fos following fear conditioning. However, this part of the PAG is not critical for the autonomic responses to conditional fear stimuli. The amygdala, predominantly through projection emanating from the CeA, exerts control over species-specific defensive behaviors organized by the PAG.

Brain Stem. The CeA sends projections throughout the brain stem. One function of these projections is to provide control over autonomic function. For example, stimulation of the rabbit’s CeA causes a heart rate deceleration mediated by monosynaptic projections to the dorsal motor nucleus of the vagus. This response mimics the bradycardia rabbits show to conditional fear stimuli, which also depends on the CeA.

While amygdala lesions block the bradycardiac conditional response to the stimulus paired with electric shock, it is important to note that these lesions do not affect baseline heart rate or the unconditional heart rate orienting response to the conditional stimulus in rabbits. Thus, projections from the CeA to brain stem autonomic nuclei may mediate parasympathetically controlled conditional responses.

Amygdala stimulation enhances reflexes organized in the brain stem such as eyeblink and startle. There are both mono- and disynaptic projections from the CeA to the nucleus reticularis pontis caudalis, which is the part of the brain stem acoustic startle circuit that is modulated by conditional fear stimuli. It has previously been shown in rats, cats, rabbits, and monkeys, using various anterograde tracers, that CeA neurons project to brain stem areas including the NTS. These results provide conclusive evidence for a GABAergic pathway from the CeA to the NTS. Although lesions of the amygdala block the ability of fear stimuli to modulate reflexes, it is important to note that the reflex itself is left intact.

Thus, projections from the CeA to several brain stem regions allow for widespread modulation of autonomic function and reflexive behaviors.

Cortex. In addition to the amygdala receiving substantial cortical projections, recent work suggests that it is in a position to exert widespread influence over cortical activity. Based on anterograde tracer studies, the LA provides strong, topographically organized inputs to the ventral and dorsal perirhinal cortices. The LA also provides a moderate input to the infralimbic cortex as well as to the ventral agranular insula. Projections from the BLA to the frontal cortex are more widespread than those from any other amygdaloid nucleus.

The CeA sends substantial ascending projections to the cholinergic basal forebrain, which in turn projects diffusely to virtually all cortical regions. Basal forebrain stimulations produce desynchronization of cortical EEG, as does CeA stimulation. Basal forebrain stimulation supports associative changes in receptive field properties of auditory cortical neurons. Based on these findings, it has been suggested that cholinergic modulation of cortical activity, mediated by amygdala projections to the basal forebrain, is critical for the induction of the stimulus-specific changes in cortical receptive fields observed during Pavlovian fear conditioning.

Hippocampal Formation. In addition to modulating cortical dynamics, the amygdala also exerts a strong influence over hippocampal activity. The hippocampus is considered to be particularly susceptible to chronic stress because it is heavily enriched with corticosteroid receptors and it participates in the termination of stress responses via the glucocorticoid-mediated negative feedback of the hypothalamus-pituitary-adrenocortical (HPA) axis.

Because this medial temporal lobe structure is crucial for declarative-explicit memory in humans and spatial-relational memory in rodents, evidence is emerging that stress generally impairs hippocampal-dependent memory tasks in both humans and rats. Lesions of the BLA attenuate the induction of longterm potentiation (LTP) in the dentate gyrus, while BLA stimulation significantly facilitates LTP induction. Recent findings indicate that amygdalar activity is crucially involved in the emergence of stress-induced impairments in hippocampal LTP and hippocampal-dependent spatial memory in rats.

The critical period of the amygdalar contribution to stress effects on hippocampal functions was determined by applying muscimol either before or immediately after stress. Results indicate that intra-amygdalar muscimol infusions before restraint tailshock stress effectively blocked stress-induced physiological and behavioral effects. Thus, the amygdala plays a critical role in the induction of cortical- and hippocampal-dependent processes thought to underlie learning and memory.

Summary. The CeA, which receives input from most of the amygdala nuclei, projects to regions responsible for autonomic, hormonal, and behavioral responses. In this way, the amygdala is in a position to muster the full arsenal of the body’s responses to stress.