Biopsychosocial Psychiatry

John H. johnhkm at overhere.com.au
Mon Aug 26 02:59:26 EST 2002


Not "every psychological quirk" but enough that we should take such
possibilities into account because reduced stress coping can be a marker of
a number of underlying propensities (ptsd, schizophrenia, depression,
bipolar). I am not specifically thinking of genetic predispositions, there
is a range of factors associated with psychopathology eg. schizophrenia.
Recent Australian study claimed that incidence of schizophrenia correlated
with the sunlight exposure of the mother during pregnancy. This spookily is
like the MS studies indicating sunlight - vitamin D intake also showed a
correlation with MS incidence. MS is an established autoimmune disease, the
evidence for that re schizophrenia is scant though I recall articles showing
elevated autoantibodies to human hsp 70 & 60 in schizophrenia. As both of
the hsps are involved in neuroprotection immunological assaults on these
hsps suggests a dysfunction. However, as both these hsps are highly
expressed in neurodegeneration the production of antibodies to these hsps
may facilitate early identification of dying cells and accelerate
phagocytosis of the same. Given the ubiquity of hsps one wonders if the
autoimmune response to these hsps in schizophrenia is confined to the CNS.
Seems to be the case but some bacterial infections have been shown to induce
autoantibodies to hsp 60; that early viral infection - autoimmune link,
particularly in the first year of life when the infants immune system is
maturing.

A recent publication has demonstrated a remarkable link between genes and
environment.

Molecular Psychiatry
2002, Volume 7, Issue 6

Early maternal deprivation reduces the expression of BDNF and NMDA receptor
subunits in rat hippocampus
M Roceri, W Hendriks, G Racagni, B A Ellenbroek and M A Riva

Using a mouse model that recapitulates many features of schizophrenia, the
authors showed that early maternal deprivation resulted in long term
declination of BDNF and NMDA receptor subunits in the hippocampus. I find
this interesting because in a recent study

Nature Neuroscience
Published online: 6 May 2002, doi:10.1038/nn853
June 2002 Volume 5 Number 6 pp 539 - 545

A rapid switch in sympathetic neurotransmitter release properties mediated
by the p75 receptor

it was demonstrated that BDNF changed an excitatory sympathetic neuron
myocte to an inhibitory mode after 15 minutes of transfusion. This action is
mediated via p75 which allows for ceramide release and nfkb transcription.
The jury is still out but it appears that while sustained expression of
these factors can precipitate cell death the primary function is protective
and it is believed the known neuroprotective effects of tnfa are mediated
via the p75 receptor. Its a broad stretch, from myocyte to CNS but makes me
curious because some studies have indicated that in early onset childhood
schizophrenia attentional difficulties are apparent and loss of inhibitory
function may be significant here..

The loss of BDNF in the hippocampus, apart from reducing neuroprotective
mechanisms, may limit LTP creation. Mattson somewhere has demonstrated that
hippocampal LTP is dependent on nfkb transcription and while some hold the
position the hippocampal LTP is solely about memory I am inclined to the
view that it also plays an integral role in attentional matters.
Additionally, NMDA activity is supported by nfkb transcription and

Neuron, Vol. 24, 401-414, October, 1999,
Essential Role for TrkB Receptors in Hippocampus-Mediated Learning.

The hippocampus is very susceptible to stressors, I believe it contains the
highest density of glucocorticoid receptors in the human CNS. These
receptors are of two classes, MR and GR. MR is activated at low levels of
gcs and I think has a 10:1 binding preference over GR. However once gcs
reached a certain concentration gr occupation will occur and gr occupation
anatagonises nfkb transcription. MR enhances nfkb, I find it interesting
that:

Neuroendocrinology 1992 Jun;55(6):621-6 Related Articles, Books


Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA
expression in rat hippocampus in vivo.

and some other studies I've seen showing how therapeutic drugs often induce
neuroprotective functions. Eg

The Mood-Stabilizing Agents Lithium and Valproate Robustly Increase the
Levels of the Neuroprotective Protein bcl-2 in the CNS
Guang Chen, Wei-Zhang Zeng, Pei-Xiong Yuan, Li-Dong Huang, Yi-Ming Jiang,
Zhen-Hua Zhao, and Husseini K. Manji

Bcl2 is an intracellular membrane related protein that plays a critical role
in regulating cell death, it is believed some cancer cells defeat apoptosis
via increased bcl 2 expression, which has been consistently shown to provide
cellular protection.
and,

Journal of Neurochemistry 79 (1), 63-70
© International Society for Neurochemistry
Dopamine mediates striatal malonate toxicity via dopamine
transporter-dependent generation of reactive oxygen species and D2 but not
D1 receptor activation

These, together with other studies show how even the administration of
antioxidants, omega 3's(antiflammatory effect), and drugs that reduce
immunological activation can have a significant bearing on outcomes. This
contrast between mr and grs is also interesting because of a study I looked
at sometime ago that indicated mild stress for up to 6 hours enhances
cognitive function but beyond that a slight declination sets in. Sustained
significant stress may saturate mr availability leading to gr occupation and
subsequent deleterious effects. All the moreso given gr occuatpion decreases
bcl 2 expression ...

Sustained stress also disrupts pfc dopaminergic function(which may allow
hippocampal over activation, not sure), given recent findings re loss of
Darrp 32 in shizophrenia(only in dorsolateral), I wonder if the loss of
severe dopaminergic regulation is an advanced stage of the disease
particularly as this study was on deceased schizophrenics.

In that Nature 1998 article re cortisol levels and hippocampal atrophy the
researchers noted cortisol levels correlated with memory and hippocampal
atrophy. Not only via LTP neuroprotection inhibition, sustained cortisol
also reduce neurogenesis in the dentate gyrus, and the emerging concensus
now is that this region 'feeds' the hippocampus with new cells, one
researcher claiming up to 5,000 per day. Certain evolutionary sense in that
because the hippocampus is amongst the hardest working areas of the brain,
has the highest density of NMDA receptors (associated EAA and NO, both
potentially neurotoxic), and the highest gc levels. So if any area of the
human brain needs fresh cells that's it.

I can't find this article but I do remember reading how early maternal
deprivation can lead to altered cortisol response but only later in life ...
. It is as if this alteration can be hidden for quite some time. Early life
events(eg. first trimester) and diet can have a important effects on later
development
or contribute significantly to disease progression. In recent imaging
studies of early childhood onset schizophrenia however, the massive cell
loss across many regions of the CNS suggests that this much more than
something that could ever be mediated by stress or life experience;
particularly for people in their teens when the HPA axis at least tends to
have a better balance (some suggestion that with age or repeated stressors
it gradually leans the wrong way).  The cell loss is substantial and rapid.
Recent news report also claimed that schizophrenics had a change in the
microglial cells leading to over activation, this seems promising because
the cell loss in shizophrenia is widespread and clearly immunological
elements are involved. This is interesting given the autoantibodies to
hsps(not in all patients) and the sunlight qtn because sunlight via vit D
generates TGFb which suppresses immunological activation.

Even mild head trauma has some association with reduced cognitive capacities
under stress and transient symptoms in the absence of any identifiable
organic abnormality. One study showed altered cortisol responses as a result
of mild head trauma and this appears to a frequent occurrence in TBI though
the cause of this remains unknown; the only hint I have seen is that even
remote trauma can affect PVN afferents thereby disrupting the HPA axis.
Environmental factors can also affect TBI outcome: eg brain injured children
from not so good families have poorer long term outcomes, the constant
stressors during the recovery period make for a poorer prognosis.

Stress impacts on most psycho pathologies. Reasons are varied and complex,
beyond me. Except in depression, where less extreme stresses induce serious
mental illness I would keep in mind the possibility of underlying
contributors; even a bad mommy.

As usual, its incredibly complicated, enough to make me insane so I'm going
back to my computer game.


John H.


"Nick Medford" <nick at hermit0.demon.co.uk> wrote in message
news:EeS+5JAQoRZ9EwVM at hermit0.demon.co.uk...
> In article <k7_89.15199$Cq.610323 at ozemail.com.au>, John H.
> <johnhkm at overhere.com.au> writes
> >Mr. Medford,
> >
> >Good to see you back. Yes, the research is replete with examples of how
> >stress can exacerbate mental illness. Stress has been associated with
poor
> >performance on testing over sustained periods or intense effort,
> >particularly in relation to TBI. Where it appears to cause mental
illness,
> >do you think perhaps it has just surfaced the latent pathology?
> >
>
> I think the idea of "latent pathology" is conceptually questionable in
this
> context. Certainly stressors may exacerbate pre-existing tendencies, one
> example would be PTSD, where it is often claimed that people do not
> develop PTSD unless they had some neurotic predisposition before the
> traumatic event. Personally I don't believe this is always true but it is
> certainly true in some cases. But- whether it is useful or even accurate
to
> describe such a predisposition as "latent pathology" I'm not sure. We get
> onto dangerous ground if every psychological quirk or vulnerability is
> held up to be "latent pathology".
>
> regards
> --
> Nick Medford









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