Which of the following is the component of the limbic system that plays an essential role in the

Limbic System, Hypothalamus and Pituitary Gland

Following the isocortical mantle over the hemisphere to its medial edges, the structures of the limbic system are encountered. These include the amygdala, hippocampus, parahippocampal gyrus, cingulate gyrus, subcallosal gyri and associated structures.

Limbic structures are associated with memory processing, emotional responses, fight-or-flight responses, aggression and sexual response—in summary, with activities contributing to preservation of the individual and the continuation of the species. The limbic system is often somewhat misleadingly described as a phylogenetically ancient part of the brain: the hippocampus is unequivocally a mammalian innovation, whereas the isocortex itself has equally ancient antecedents.

The key limbic structures are located in the mesial temporal lobe and these are readily identified with MRI. The amygdala is the most anterior structure, separated from the hippocampal head by the uncal recess of the temporal horn (Fig. 53.10). The medial-lying uncus (hook) has anterior amygdaloid and posterior hippocampal components.

The hippocampal head, body and tail are well shown on coronal imaging along with the parahippocampal gyrus (Fig. 53.11).

The white matter connections of the hippocampus via the fimbria-fornix system are visualised on coronal and sagittal images. A thinned layer of grey matter called the indusium griseum arches over the corpus callosum to the hippocampi but is not visible on standard imaging.

The hypothalamus forms the floor of the third ventricle and its side walls anteriorly, following an oblique line inferiorly from the foramen of Monro to the midbrain aqueduct. It consists of a group of nuclei serving a number of autonomic, appetite-related and regulatory functions for the body, as well as controlling and producing hormonal output from the pituitary gland. The hypothalamus is intimately linked to other limbic structures and might be considered the output for the limbic system.

The pituitary infundibulum (or stalk), a hollow conical structure, extends inferiorly from the hypothalamus to the pituitary gland. The pituitary gland varies considerably in size, with sometimes only a thin rim of glandular tissue visible at the floor of the pituitary fossa. In young females, the gland may fill the fossa with a convex upper border. Anterior and posterior lobes of the pituitary gland can be distinguished on MRI, the posterior lobe normally returning high signal on T1 weighted images due to neurosecretory granules in the neurohypophysis (the pituitary ‘bright spot’). Both gland and stalk show strong contrast enhancement.

The limbic system

The limbic system consists of a group of structures clustered around the thalamus. These include the hypothalamus; the hippocampus (Greek, sea horse); the amygdala (Latin, almond); and the cingulum bundle connecting the hippocampus with the frontal cortex.

There is evidence that the limbic structures control the motivational or behavioural responses to pain together with the emotional response to it or what may be called its affective dimension. With respect to the latter, it is the extent to which the limbic system becomes activated in response to any given noxious stimulus that determines how much any particular individual suffers from it – in other words, the degree to which it hurts that person. It is therefore activity in the limbic system that governs a person's pain tolerance.

Functional Anatomy of the Limbic System—Key Position of the Hypothalamus

Figure 59-4 shows the anatomical structures of the limbic system, demonstrating that they are an interconnected complex of basal brain elements. Located in the middle of all these structures is the extremely smallhypothalamus, which from a physiological point of view is one of the central elements of the limbic system.Figure 59-5 illustrates schematically this key position of the hypothalamus in the limbic system and shows other subcortical structures of the limbic system surrounding it, including theseptum, paraolfactory area, anterior nucleus of the thalamus, portions of the basal ganglia, hippocampus, andamygdala.

Surrounding the subcortical limbic areas is thelimbic cortex, composed of a ring of cerebral cortex on each side of the brain—(1) beginning in theorbitofrontal area on the ventral surface of the frontal lobes, (2) extending upward into thesubcallosal gyrus, (3) then over the top of the corpus callosum onto the medial aspect of the cerebral hemisphere in thecingulate gyrus, and finally (4) passing behind the corpus callosum and downward onto the ventromedial surface of the temporal lobe to theparahippocampal gyrus anduncus.

Thus, on the medial and ventral surfaces of each cerebral hemisphere is a ring of mostlypaleocortex that surrounds a group of deep structures intimately associated with overall behavior and emotions. In turn, this ring of limbic cortex functions as a two-way communication and association linkage between theneocortex and the lower limbic structures.

Many of the behavioral functions elicited from the hypothalamus and other limbic structures are also mediated through the reticular nuclei in the brain stem and their associated nuclei. We pointed out inChapter 56, as well as earlier in this chapter, that stimulation of the excitatory portion of this reticular formation can cause high degrees of cerebral excitability while also increasing the excitability of much of the spinal cord synapses. InChapter 61, we see that most of the hypothalamic signals for controlling the autonomic nervous system are also transmitted through synaptic nuclei located in the brain stem.

An important route of communication between the limbic system and the brain stem is themedial forebrain bundle, which extends from the septal and orbitofrontal regions of the cerebral cortex downward through the middle of the hypothalamus to the brain stem reticular formation. This bundle carries fibers in both directions, forming a trunk line communication system. A second route of communication is through short pathways among the reticular formation of the brain stem, thalamus, hypothalamus, and most other contiguous areas of the basal brain.

Escape, avoidance and safety

The limbic system regulates the appraisal of an event and therefore raises the alarm in the face of danger. The amygdala signals to the hypothalamus that a threat has been detected, leading to autonomic arousal and activation of the stress response. The role of the amygdala in threat detection is well established [12–14]. The ability to effectively detect and respond with urgency to threats in the environment requires a type of associative learning whereby changes in synaptic strength occur in the amygdala itself.

This form of associative learning, or conditioning, underlies our experience of fear when a threat is detected. Fear conditioning is therefore a form of implicit, or nondeclarative, learning that produces automatic and unconscious responses to stimuli. Disruption of amygdala activity is implicated in certain neuropsychiatric diseases, where a deficit in fear learning is observed [15,16].

Fear conditioning is the driving force behind the escape response that is observed in all animal species when danger is detected. In humans, specifically, this escape response has been intimately linked to avoidance behaviour, whereby a stimulus that carries aversive qualities is avoided in future encounters. Avoidance is therefore a product of a type of negative reinforcement. This means that a desirable outcome, i.e. the avoidance of harm, is achieved when avoidance behaviour results in the aversive stimulus not being encountered.

As such, the acquisition and maintenance of avoidance behaviour becomes deeply engrained through a two-stage process that entails both classical and operant conditioning [17]. Specifically, the process involves the association of a previously neutral stimulus with an aversive event, with the previously neutral stimulus subsequently evoking a fear response. The second stage involves the reinforcement of the fear evoked by the previously neutral stimulus, which has effectively taken on the properties of the aversive event with which it has effectively been paired. This, in essence, provides an accurate behavioural model of avoidance behaviour as well as maladaptive fear conditioning that takes place in the development of specific and social phobias [18].

A well-known study demonstrating this model of avoidance behaviour in relation to the acquisition of a specific phobia is that of the Little Albert study [19]. Not much is known about the infant who, since the study was published, has been famously referred to by the pseudonym Little Albert. The experimental design involved a conditioning paradigm whereby the infant, the sole participant in this study, was presented initially with a live white rat. Baseline reactions to the white rat were recorded and showed no discomfort or agitation in the presence of the rat; instead the infant seemed quite curious by the furry creature's presence. The rat, therefore, was considered a neutral stimulus in this scenario.

The next phase of the experiment involved exposing the infant to an aversive auditory stimulus, a loud noise, which, as anticipated, produced a startle response in the infant. Over a series of trials that followed, the aversive auditory stimulus was paired with the rat. With time, the aversive stimulus was removed from the scenario, but the aversive qualities of the auditory stimulus had been successfully paired with the previously neutral stimulus. Presentation of the white rat alone then produced the conditioned startle response. The study effectively illustrated how a phobia could be acquired and maintained through the process of associative learning. Furthermore, the maintenance of rigid avoidance behaviour has been found to play a profound role in the pathophysiology of anxiety disorders such as obsessive-compulsive disorder (OCD) [20,21].

A recent psychological model of stress, however, suggests that previous accounts have overemphasised the importance of aversive stimuli, or events, in triggering the stress response while ignoring the importance that the perception of safety, or the lack thereof, may play in this process. Brosschot et al. (2018) have introduced the generalised unsafety theory of stress, or GUTS, which emphasises the importance that perceived safety plays in regulating the stress response [22]. According to the model, the stress response is always active, or rather on constant standby, but is inhibited through perceived safety in the environment. The prefrontal cortex (PFC), crucial in decision-making and mediating behaviour, inhibits the stress response by keeping the ‘brakes’ on the amygdala during times of safety. In the absence of a safety cue or signal, the PFC is hypothesised to lift the brake on the amygdala, unleashing the stress response.

This account is consistent with early behavioural models on conditioned inhibition, where avoidance learning is not merely dependent upon the presence of stimuli that signal an aversive event but rather the presence of stimuli that signal a period of safety from the aversive event [23]. The GUTS model focuses on how safety signals are primary learned through the social context and how social environments may shape adaptive as well as maladaptive reactions to stress. Appraisal of the social context, therefore, is considered to be intricately linked to the experience of stress and pathological anxiety.

While the model retains the focus on appraisal, albeit of safety cues as opposed to aversive stimuli, it differs from earlier models of stress, suggesting that the appraisal of environmental cues lifts the brakes on a system that is quietly running in the background, as opposed to the parasympathetic division hitting the brakes on the system that was initially dormant and only activated once danger had been detected. Whether brakes are being lifted or applied, what appears to be regulating the entire process is the meaning that we ascribe to stimuli, events and cues in our environment. To better understand this rather complex relationship between the psychological and the physiological, a good starting point would be to explore further the basic physiology of stress.

Topographical anatomy of the hypothalamus

The hypothalamus is the most ventral part of the diencephalon, lying beneath the thalamus and ventromedial to the subthalamus (Fig. 16.1; see alsoFigs 12.1–12.3Fig. 12.1Fig. 12.2Fig. 12.3). It forms the floor and the lower part of the lateral wall of the third ventricle, below the hypothalamic sulcus (seeFig. 12.2). On the base of the brain, parts of the hypothalamus can be seen occupying the small area circumscribed by the crura cerebri, optic chiasm and optic tracts (seeFig. 12.1). Between the rostral limits of the two crura cerebri, on either side of the midline, lie two distinct, rounded eminences, themammillary bodies, which contain the hypothalamicmammillary nuclei. In the midline, immediately caudal to the optic chiasm, lies a small elevated area known as thetuber cinereum, from the apex of which extends the thininfundibulum (infundibular process), orpituitary stalk. This is attached to thepituitary gland (hypophysis), a pea-sized structure which lies within the hypophyseal fossa (sella turcica) of the sphenoid bone (seeFigs 5.1,5.4). The pituitary gland consists of two major, cytologically distinct, parts: the posterior pituitary orneurohypophysis and the anterior pituitary oradenohypophysis (Figs 16.2,16.3). The posterior pituitary is a neuronal structure, being an expansion of the distal part of the infundibulum. The anterior pituitary is not neural in origin. The two parts are, however, closely linked by thepituitary (hypophyseal)portal system of vessels (Fig. 16.3), which are derived from the superior hypophyseal artery. Releasing factors, which are synthesised in the hypothalamus, pass to the adenohypophysis through these vessels to control the release of anterior pituitary hormones.

The hypothalamus is able to integrate interoceptive signals from internal organs and fluid-filled cavities and make appropriate adjustments to the internal environment by virtue of its input and output systems.

Input to the hypothalamus is both circulatory and neural in origin (Fig. 16.4). The circulating blood provides physical (temperature, osmolality), chemical (blood glucose, acid–base state) and hormonal signals of the state of the body, its growth and development and its readiness for action. (e.g. sex, suckling, defence, escape, etc.). Neural signals come from a number of sources. The largest input originates from limbic structures, the hippocampus and the amygdala. Fibres of hippocampal origin constitute the fornix, a large component of which terminates in the medial mammillary nucleus within the mammillary body (Figs 16.5–16.7). Fibres from the amygdala to the hypothalamus run in the stria terminalis (seeFig. 12.3). The nucleus solitarius of the medulla projects to the hypothalamus, conveying information collected by the autonomic nervous system concerning the pressure within the smooth-muscled walls of organs (baroreceptors) and the chemical constituents of the fluid-filled cavities (chemoreceptors). The state of arousal is communicated by connections that originate in the brainstem. Monoaminergic projections ascend in the medial forebrain bundle (seeFig. 9.14) and the reticular formation provides input both directly and indirectly via the thalamus.

Limbic System Anatomy

The noncortical areas that are part of the limbic system include the following (Figure 15-3):

Amygdala

Septal nuclei

Basal ganglia

Thalamus

Hypothalamus

Limbic midbrain

Olfactory system

Extensive texts discuss the limbic system in detail; however, for our purpose, one important circuit (of Papez) and hippocampal formation are briefly discussed here because they are important for understanding changes in temporal lobe epilepsy.

Regulatory Systems

Many neurotransmitter systems from the brain stem, limbic system, and other areas of the hypothalamus convey information to GnRH neurons (Fig. 7-30). These afferent systems include neurons that contain norepinephrine, dopamine, serotonin, GABA, glutamate, endogenous opiate peptides, NPY, galanin, and a number of other peptide neurotransmitters. Glutamate and norepinephrine play important roles in providing stimulatory drive to the reproductive axis, whereas GABA and endogenous opioid peptides provide a substantial portion of the inhibitory drive to GnRH neurons. Influences of specific neurotransmitter systems are discussed where appropriate in the following sections, which cover the physiologic regulation of GnRH neurons.

GnRH neurons are surrounded by glial processes, and only a small percentage of their surface area is available to receive dendritic contacts from afferent neurons. Changes in the steroid hormone milieu influence the degree of glial sheathing and may play important roles in regulating afferent input to GnRH neurons by this mechanism.43,45 Some glial cells also secrete substances including transforming growth factor-α and prostaglandin E2 that can modulate the activity of GnRH neurons.

IV. Hypothalamus

The hypothalamus is a neural component of the limbic system. As such, the hypothalamus acts as a signaling organ, adapting the body to various environmental stresses. It is unique because neural projections interface directly with the blood, thereby directly secreting hormones and releasing factors into the bloodstream, ultimately inducing systemic changes. The hypothalamus controls many of the autonomic and endocrine functions of the body.

The hypothalamus regulates endocrine function in two ways. First, endings of nerve axons that arise in the supraoptic and paraventricular nuclei of the hypothalamus project to the posterior pituitary. Generation of action potentials in these nerves results in the release of oxytocin or vasopressin (antidiuretic hormone) directly. Therefore, the hypothalamus functions as an endocrine organ. Second, the hypothalamus synthesizes releasing hormones that are discharged into the capillary network of the median eminence of the hypothalamus. The capillaries then converge into portal veins and empty into the sinusoids of the anterior lobe of the pituitary. The releasing hormones interact with their receptors in the anterior pituitary, where they either stimulate or inhibit the secretion of a particular pituitary hormone. Table II lists the hypothalamic releasing hormones and the known actions of these releasing factors on the anterior pituitary.

Table II. Hypothalamic Releasing Hormones and Their Effects on the Anterior Pituitary

As can be garnered from examination of the summary of effects of the hypothalamic releasing hormones, oxytocin and vasopressin, disruption of the normal function of the hypothalamus would generate secondary endocrine insufficiencies by virtue of the lack of trophic actions of the hormones or releasing factors on peripheral endocrine glands or organs. Hypothalamic deficiencies can be created in two ways. First, the animals can undergo a complete hypophysectomy. Hypophysectomized animals are generally purchased at a young age, with this procedure already performed prior to shipment from large breeding firms. The problem with this approach is that all hormones and hormone releasing factors of the hypothalamus are adversely affected. One may wish to induce a growth hormone deficiency, for example, but numerous other endocrine systems would also be affected. Second, areas of neurons within a certain region of the hypothalamus can be lesioned. This would represent a more neurosurgical approach to dissecting out only those hormones or releasing factors that you wish to remove. For example, somatostatin-containing neurons are particularly abundant in the anterior periventricular region, whereas growth hormone-releasing hormone is synthesized in the cell bodies of neurosecretory neurons of the arcuate and ventromedial nuclei of the hypothalamus. The problem with this approach is that it is virtually impossible to eliminate only the selected neurons of interest.