Limbic System And Long-Term Potentiation
Anatomy of the limbic system
Many different definitions of the limbic system exist, and in this chapter we will be restricting our definition to structures that lie primarily along the medial aspect of the temporal lobe: cingulate gyrus, parahippocampal structures (postsubiculum, parasubiculum, presubiculum and perirhinal cortex), entorhinal cortex, hippocampal complex (dentate gyrus, CA1–CA4 subfields and subiculum), septal nuclei and the amygdala. Additional structures closely associated with the limbic system include the mammillary bodies of the hypothalamus, the olfactory cortex and the nucleus accumbens (see Chapters 11, 30, 42 and 47, respectively).
The anatomical organization of the limbic system indicates that it performs some high level processing of sensory information, given its input from the associative cortical areas (see Chapter 34). The predominant outflow of the limbic system is to the prefrontal cortex and hypothalamus as well as to cortical areas involved with the planning of behaviour, including motor response (see Chapters 35 and 38). Thus, anatomically the limbic system appears to have a role in attaching a behavioural significance and response to a stimulus, especially with respect to its emotional content. The hippocampal complex has been shown to have both a high degree of susceptibility to hypoxia and yet a remarkable degree of plasticity, which helps explain why this structure is important in the generation of epileptic seizures (see Chapter 61) as well as memory acquisition. It is also one of the major sites for neurogenesis in the adult brain, which may also be important in some forms of memory and mood functions.
Functions of the limbic system Hippocampal complex and parahippocampal structures (see also Chapter 46)
The original description in the 1950s by Scoville and Milner of patient HM with bilateral anterior temporal lobectomy and a resulting profound amnesic state suggested that this area of the brain had a major role in memory. Subsequently, the hippocampus proper and parahippocampal areas were shown to have a role in the acquisition of information about events (see Chapter 46), although the major role of the hippocampus itself probably relates more to spatial memory.
However, the long-term storage of memories occurs at a distant site, probably within the overlying cerebral cortex – as demonstrated by the pattern of memory loss seen in dementia of the Alzheimer type (DAT; see Chapter 60), namely well-preserved retrograde memory (for distant events such as childhood) in the face of severely impaired or absent anterograde memory (inability to remember what the patient has just done).
Amygdala (see also Chapter 47)
The amygdala is a small, almond-shaped structure made up of many nuclei that lies on the medial aspect of the temporal lobe. Damage to this structure experimentally leads to blunted emo- tional reactions to normally arousing stimuli, and can even prevent the acquisition of emotional behaviour. In humans with selective amygdala damage there appears to be a profound impairment in the ability to recognize facial expressions of fear. Conversely, stimulation of this structure produces a pattern of behaviour typical of fear with increased autonomic activity. This is sometimes seen clinically in temporal lobe epilepsy, in which patients complain of brief episodes of fear.
The cingulate gyrus running around the medial aspect of the whole hemisphere has a number of functions, including a role in complex motor control (see Chapter 38), pain perception (see Chapters 32 and 33) and social interactions. Damage to this structure can produce motor neglect, as well as reduced pain perception, reduced aggressiveness and vocalization, emotional blunting and altered social behaviour which can result in a clinical state of akinetic mutism (not talking or moving). Stimulation of this area, either experimentally or during an epileptic seizure, produces alterations in the autonomic outflow and motor arrest, with vocalization and complex movements.
Long-term potentiation (LTP) is defined as an increase in the strength of synaptic transmission with repetitive use that lasts for more than a few minutes, and in the hippocampus it can be trig-gered by less than 1 second of intense synaptic activity and lasts for hours or much longer. It can be induced at a number of CNS sites but especially the hippocampus, and it has therefore been postulated to be important in memory acquisition. However, different mechanisms may underlie LTP at different synapses within the hippocampal complex, and most of the work is based on the excitatory glutamate synapse in the CA1 subfield of the hippocampal complex.
The current model of LTP is as follows:
Stage 1 (see figure): An afferent burst of activity leads to the release of glutamate from the presynaptic terminal.
Stages 2 and 3: The released glutamate then binds to both N- methyl-D-aspartate (NMDA) and non-NMDA receptors in the postsynaptic membrane. These latter receptors lead to a Na+ influx (stage 2) which depolarizes the postsynaptic membrane (stage 3). Stage 4: The depolarization of the postsynaptic membrane not only leads to an excitatory postsynaptic potential (EPSP), but also removes Mg2+ from the NMDA-associated ion channel.
Stage 5: The Mg2+ normally blocks the NMDA-R associated ion channel and thus its removal in response to postsynaptic depolarization allows further Na+ and Ca2+ influx into the postsynaptic cell.
Stage 6: The Ca2+ influx leads to the activation of a postsynaptic protein kinase, which is responsible for the initial induction of LTP – a postsynaptic event.
Stage 7: The maintenance of LTP, in addition to requiring a persistent activation of protein kinase activity, the insertion possibly of more postsynaptic glutamate receptors (stage 7a) and changes in gene transcription (stage 7c), may also require a modification of neurotransmitter release (stage 7b), i.e. an increase in transmitter release in response to a given afferent impulse. The presynaptic modification, if necessary in the maintenance of LTP, means that the postsynaptic cell must produce a diffusible secondary signal that can act on the presynaptic terminal such as permeant arachidonic acid metabolites, nitric oxide, carbon monoxide and platelet activating factor.
In some circumstances long-term depression (LTD) can be induced in the mossy fibre synapses in the CA3 subfield of the hippocampus. This, in contrast to LTP, is thought to be mediated by a presynaptic metabotropic glutamate receptor.