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.
Cingulate gyrus
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
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.
