Recent theories of neurobiology of depression

1. Dr. Santanu Ghosh, MD
Assistant Professor, Psychiatry
Tripura Medical College, Agartala
Neurobiology of Depression:
Recent Updates

2. Conflict of Interests
The presenter declares that there is no conflict of interests
regarding the presentation of this topic

3. Introduction
Major depression is a serious disorder of enormous sociological and clinical
relevance. The discovery of antidepressant drugs in the 1950s led to the first
biochemical hypothesis of depression, which suggested that an impairment in
central mono aminergic function was the major lesion underlying the disorder.
Basic research in all fields of neuroscience (including genetics) and the discovery
of new antidepressant drugs have revolutionized our understanding of the
mechanisms underlying depression and drug action.

4. Prefrontal cortex2
Amygdala2
Hippocampus5
Nucleus accumbens4
Anterior cingulate
cortex3
Insular cortex1
Areas of the Brain Implicated in Depression
1. Kennedy SE, et al. Arch Gen Psychiatry. 2006;63:1199–1208. 2. Drevets WC. Curr Opin Neurobiol. 2001;11:240–249. 3. Whittle S, et
al. Neurosci Biobehav Rev. 2006;30:511–525. 4. Schlaepfer TE, et al. Neuropsychopharmacology. 2008;33:368–377. 5. Gaughran F, et al.
Brain Res Bull. 2006;70:221–227.

5. Neuroplasticity
• It referrers to the process
underlying neurogenesis, means
birth of new neurons.
• It includes:
Axonal Sprouting
Syneptic remodeling
Creation of new synapse
• Sites:
- Ventricles of forebrain
near olfactory bulb
- Dentate gyrus of
hippocampus (CA3 region)
• 50% of these new born cells
die and disappear
• Those that survive may be
either neuron or a glial cell
• Once the cell committed to
become a neuron, growth
factors comes in to play.
 BDNF
 IGF

6. Mechanism of neuroplasticity
Ca2+ calmudulin dependent protein kinase
cAMP dependent protein kinase
Mitogen activated protein kinase
CERB
(cAMP Reactive Element binding protein)
BDNF, FGF-2
MAP signaling pathway activation of bcl-2
expression
BDNF exerts its major neuro protective effects
through an inhibition of cell death cascade.
Acute Stress
Glutamate
Post-synaptic inotropic channels opens
↑ Intracellular Na+
Activation of NMDA receptor
Ca2+ calmudulin dependent protein kinase
Neuroplasticity

8. Neurotrophins and Depression

9. Neurotrophins in the brain
Neurotrophnis constitute a family of 4 distinct secreted
growth factors
Neurotrophin-3
Trk-C receptor
Neurotrophin-4
Trk-B receptor
Nerve Growth
Factor
Trk-A receptor
Brain-derived
Neurotrophic
Factor
Trk-B receptor
BDNF
NGF
NT-4
NT-3

10. Receptor binding of neurotrophins

11. Functions of neurotrophins
Neurotrophins
NT-3
NGF
NT-4
BDNF
Prevents naturally
occurring death and
increases expression of
neuronal markers on
embryonic motor neuron
Developing sympathetic
neurons are absolutely
dependent upon NGF
Stimulate differentiation of
motor neurons from neural
tube progenitors. NT 3 is
very important in early
embryogensis
Function of NT 4 is very
Similar to the function
Of BDNF

13. Evidences
•
Expressions of BDNF, BDNF-regulated genes,
and the receptor TrkB are decreased in post-
mortem brain samples from depressed humans
and in circulating lymphocytes of depressed
patients during a drug-free period
Decreased serum BDNF levels in MDD patients
and polymorphisms in the BDNF gene may be
predictive of the Chronicity of the disease.
Expression of BDNF is up regulated by
antidepressant treatments, including electroconvulsive
therapy and rTMS. In addition, BDNF and NT3
produced antidepressant effect on behavioral models
of depression

14. MicroRNAs and Depression

15. What is micro RNA?
• Genome generates small units of noncoding RNA, termed microRNA (miRNA).
• miRNAs are regulatory molecules which control gene function by cleaving or
repressing the translation of Neural Plasticity target mRNAs. miRNAs are very
conserved among the different species and participate critically in most biological
processes.
• Three aspects of miRNA is particularly relevant in medicine:
1. Dysregulation of specific miRNA are associated to many diseases
2. Levels of miRNA can be identified and quantified by RT-PCR in the serum
serving as biomarkers of different diseases
3. they can be silenced in vivo by administration of miRNA inhibitors
(antagomir) or employed as exogenous therapeutic agents

16. Functions of miRNA
Neuron survival
Synaptogenesis Neural
plasticity
Functions

17. Role in depression
• Alterations of various mirnas, including mir-30e, mir-182, and mir-132 have been
implicated in MDD
• Remarkably, mir-132, and mir-182 regulate negatively the expression of BDNF
and were found to show increased serum levels in MDD patients in preclinical
studies.
• Mir-212, which also regulates the expression of BDNF overexpresses in the
dentate gyrus and serum after electroconvulsive stimulation
Together these findings suggest that future functional studies of miRNA will provide
Significative advances in the understanding of psychiatric diseases including the
design of novel treatments

18. Stress Hormones and Depression

19. 19
STRESS
HYPOTHALAMUS
ANTERIOR PITUITARY
CRH
ACTH
ADRENAL GLAND
CORTISOLCATECHOLAMINE
ENDOTHELIUM & BLOOD VESSEL
•↑ Platelet activity
• Vasoconstriction
Increased
secretion of
•TNFα
• IL-1
• IL-6Adrenal sympathetic
hyperactivity
Immune System
Myocardial ischemia
Ventricular arrhythmia

20. Elevated levels of stress
and Glucocorticoid
hormones interfere with
normal hippocampal
neurogenesis
A glucocorticoid receptor
target gene, the serum-
and glucocorticoid
inducible kinase 1 (SGK1)
which inhibits
hippocampal
neurogenesis, is
unregulated in depressed
patients
DEPRESSIONClick to
add Text
Evidence for a role of
corticosteroids modifying the
function of BDNF, suggesting
a functional crosstalk
between stress hormones and
BDNF signaling of potential
implication in the
pathogenesis of MDD

21. Inflammation and Depression

22. Cytokines
• Participate in the innate immune response
and inflammation
• Have important metabolic and endocrine
effects including neurotransmitter
metabolism, neuroendocrine function, and
neural plasticity
People treated with inflammatory Cytokines
such as interferon alpha develop depression
that is indistinguishable from depression in non
-medically ill Populations
expression of different cytokines and genes
implicated in cell death is up-regulated in post-
mortem brain tissue of MDD patients suggesting
local inflammatory, apoptotic, and oxidative stress
in brain regions involved in reward-related
behaviors .

23. Expression of different cytokines and genes implicated in cell death is
up-regulated in post-mortem brain tissue of MDD patients suggesting
local inflammatory, apoptotic, and oxidative stress in brain regions
involved in reward-related behaviours
IL1, IL-8
TNF
The involvement of cytokines in behavior and in different functions of
the nervous system is also sustained by the presence of specific
receptors in hippocampus and hypothalamic nuclei
IL1, IL-8
TNF
Pro-inflammatory cytokines stimulate thehypothalamic-pituitary-
adrenal axis, activate the secretion of growth hormone, and inhibit
thyroid-stimulating hormone
IL1, IL-8
TNF
in contrast with the elevated levels in the blood, the level of
interleukin-6 in cerebrospinal fluid is reduced in MDD patients and
the decreased level is predictive of future depression in old women
IL1, IL-8
TNF

24. Gut Microbiota and Depression

25. Proposed Methodology/work plan
Brain-gut Axis
Microbiota
Present status
The microbiota can
influence brain
chemistry and
consequently behavior
At the present, we are still
far from assigning a role for
misbalances in the gut
microbiota in the
pathophysiology of MDD and
alterations in gut flora may
be secondary to abnormal
gastrointestinal dynamics in
MDD patients.
Leptin, ghrelin ,
cholecystokinin , and other
signalling peptides produced
in the gastrointestinal
system with a direct influence
on the central nervous system

26. Conclusion
There is no doubt that the mono aminergic system is one
of the cornerstones of these mechanisms, but multiple
interactions with other brain systems and the regulation of
central nervous system function must also be taken into
account. In spite of all the progress achieved so far, we
must be aware that many open questions remain to be
resolved in the future