Summary of notes structured in exam and essay format complete with point, evidence, analysis, and critical thinking. Structured based on marking criteria.
Critically discuss the evidence that the lateral habenula
and medial prefrontal cortex may play a key role in
depressive disorders. How might ketamine function as an
antidepressant at these sites?
PART 1: INTRODUCTION
Chronic stress has differential effects on brain works within the hippocampus, such as the lateral habenula
(LHb) and the medial prefrontal cortex (mPFC) that contributes to phenotypes in depressive disorders. The
lateral habenula (LHb) is a component of the diencephalon that makes up the epithalamus alongside the
pineal gland. This brain network is involved in several key processes such as reward processing, stress
adaptation, and mediating of monoaminergic neurotransmission. The medial prefrontal cortex (mPFC) is an
area of the cerebral cortex that has been associated regulatory roles in executive cognitive functions such
as inhibitory control and processing of emotion. Recent studies have identified dysfunctions within the LHb
and mPFC regions of the brain in individuals with MDD. Due to the roles of these respective regions, it is
hypothesised that impairments of these brain regions are implicated in the pathophysiology of MDD. This
essay will aim to highlight and critically evaluate the key findings that support this hypothesis. Furthermore,
it will examine the antidepressant potential of ketamine, an NMDA receptor antagonist, on the deficits seen
in both the LHb and mPFC after a chronically stressful experience.
PART 2: LATERAL HABENULA
Argument: Altered LHb functioning is associated with depression-like symptoms in animal models
Evidence: Shumake et al., 2003 higher metabolic activity in the LHb is associated with animal models
of learned helplessness
Shumake et al., (2003) bred congenitally helpless rats that, in response to stress, displayed a rapid
helpless response.
This model of depression allowed them to understand which brain structures contribute to
depression vulnerability.
Using cytochrome oxidase histochemistry, the researchers examined the difference between brain
metabolism between congenitally helplessness and non-helpless rats.
Interestingly, the congenitally helpless rats had a 64-71% increased brain metabolism
Critical Thinking:
These findings implicate overactivity of the LHb in the vulnerability to depression. LHb metabolism is
inversely related with changes in dopamine transmission. This is consistent with the monoamine
hypothesis of depression where depression-like symptoms are partially caused by reduced levels of
dopamine.
Link
This demonstrates that there is an association between LHb overactivity and depression-like
symptoms in rodent models
One question that still needs to be asked, however, is if this correlation can be extended into a
cause-effect relationship.
In order to elucidate this question, the first step is identifying whether hyperexcitability of the LHb
will confer depression-like symptom development on naïve mice.
Argument: Overexcitability of the LHb will induce depression-like symptoms in naïve mice
Evidence: Yang et al., 2018 photostimulation of the LHb drives anhedonia and behavioural despair
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