From experiment on rats

Rats are amenable to experimentation !

How does hippocampal neurogenesis loss come about?


1.
Early damage: Late releaser effect

Explanation 1.

Forsyth et al Schizophr Bull (2012) doi: 10.1093/schbul/sbs098 ... Forsyth et al

[ Of 125 survivors of severe perinatal brain damage, six (4.8%) later developed schizophrenia. ...
perinatal influence
Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. Am J Psychiatry . 1998 Mar ; 155(3):355-64 ]

The explanation is that earlier hippocampal damage, usually around birth reduces subsequent hippocampal neurogenesis activity, but not enough to upset normal development in the years before adolescence - perhaps because the parents and the home shields them from the level of anxiety that comes after losing that social protection during and after adolescence.
The greater anxiety and stress [ Snyder ] during that period of leaving home during adolescense, further lowers hippocampal neurogenesis, the hippocampal roundabout connections being now weakened, allows the coming together of the world of schizophrenia

Now a new study ... IN Rats [ Lee et al :- Neuron. 2012 Aug 23;75(4):714-24. .... ..... Early cognitive practice prevents adult deficits in a neuro-developmental schizophrenia model
[ abstract ]

Brain abnormalities acquired early, in perinatal life may cause schizophrenia like behaviour ( as it would be in rats ), characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments.

Cognitive symptoms, like impaired cognitive control, are now recognized to be important treatment targets but current cognition-promoting programmes are ineffective.

' We hypothesized that cognitive training prior to the Rat adolescent period (of neuroplastic development)
can tune compromised neural circuits to develop in the service of adult cognition
and attenuate schizophrenia-related cognitive impairments that manifest in the ( RAT )adulthood '.

Concludes:- Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia.

' We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia,
that early adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats.
The early intervention also normalized general brain function [ indicated by success in tests other than on the one trained for )

[ .,. this confirms previous rodent studies showing that neonatal hippocampal damage leads to behaviour difficulties, but only after adolescence ; in between times they develop normally.



The adult rat ability to see and search around them in a test environment is worse where there has been neonatal hippocampal damage.

The jump to the clinical service is .... if we can predict better who is going to become ill with schizophrenia, will giving them more practical experience before the illness - perhaps in areas like shopping and cooking , taking personal rsponsibility for money mangement , help them have a better life when the illness comes?


This and other similar experimental finding in rodents [

Lecourtier L
Intact neurobehavioral development but dramatic impairments of procedural-like memory following in rats.
early hippo rat lesion gives late adolescent memory problem

[ Lecourtier: Tengo ] give by analogy a possible and plausable explanation for the unaccounted 'sudden' clustering in humans of the onset of schizophrenia in adolescence and early adulthood. It perhaps explain the slightly later onset of the illness in women than in men.
[ ? They leave the nest better informed in personal and domestic care !? ]

It also accounts to some extent for the finding that schizophrenia is six times more likely in people who have epilepsy, and people with schizophrenia are more likely to have epilepsy. [ epilepsy and schizophrenia ]

Both have in common the vulnerability of the hippocampal area of the temporal lobe to damage - from low birth weight, from periods of hyoxia during birth ; from vertebral artery occlusion; from herniation of the upper brain through the tentorial tent because of pressure from oedema swelling above the tentorium within the enclosed resistant skull
"Our results point to preserved neurobehavioral development after the lesion over the time before adolescence. Progress till adolescence is normal; it is not a gradual failing after the initial lesion

. So what happens in adolescence is triggered then in some other way at the time of adolescence, not before Finally, they show for the first time that NVHL disabled the development of behavioral routines, suggesting dramatic procedural memory deficits.

The presence of procedural memory deficits in adult rats subjected to NHVL suggests that the lesions lead to a wider range of cognitive deficits than previously shown.
Interestingly, procedural or implicit memory impairments have also been reported in schizophrenic patients
.


Teng KY et al early lesion: late effect Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208, USA.

consequences. Animals with a neonatal ventral hippocampal lesion (NVHL) develop abnormal behaviors during or after adolescence,
suggesting that early insults can have delayed


Explanation 2.

How come hippocampal neurogenesis failure ( and consequences ). Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus,
but the genes and molecular mechanisms accounting for this have been challenging to identify.

Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies.
In mice, C4 mediated synapse elimination during postnatal development.

These results implicate excessive complement activity in the development of schizophrenia.
It may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
?

It may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia'.
Nature August 2011 Volume: 476, Pages: 458-461 Jason S. Snyder et al

Why and how does stress break down schizophrenia ???

........ ' The hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis'

Stress -
[ a membrane which spreads across between the cortex area, and the mid brain ]

if not High Expressed Emotion - one of the most robust associations with breakdown in schizophrenia !!! ???

The factual bit is the effect on dental cell neurogenesis
Add that effect on to reduced dental neurogenesis in schizophrenia, then you get a further down turn onto the already reduced neurogenesis in the hippocampus in schizophrenia .
Snyder







There is enough working memory capacity to get through the ages when and where their support system - i.e. the parental guidance from territorial history and instinct - is in control - - but when the individual has to go off under their own steam, behaviour falters and is aberrant !!!!!
The difficulties with the outside world have to be done by the 'emancipated' with Working Memory Capacity, already less after neonatal damage but sufficient to cope in sheltering environment - further reduced by the level of stressful anxiety coming from the inablity to cope on their own with the living complexity,
[ from stress - see what follows below ]

Obstetric abnormalities: schizophrenia
for and against
neonatal jaundice

The work of O’Donnell [ Pharmacology & Therapeutics 133 (2012) 19–25 ] and others is particularly important here as this group has shown that neonatal hippocampal lesions impair dopaminergic innervation of the prefrontal cortex during adolescence. This is therefore direct evidence that an early postnatal intervention that is believed relevant to schizophrenia can induce late (adolescence) developmental alterations in DA ontogeny.


neonatal ventral hippocampal lesion (NVHL) develop abnormal behaviors during or after adolescence,
suggesting that early insults can have delayed consequences.

"Intact neurobehavioral development and dramatic impairments of procedural-like memory following neonatal ventral hippocampal lesion in rats".


Again ..... Lecourtie3 L. et al
Neuroscience. 2012 Jan 27;
Laboratoire d'Imagerie et de Neurosciences Cognitives, UMR, 7237 Université de Strasbourg/CNRS, Strasbourg, France.
Abstract
Neonatal ventral hippocampal lesions (NVHL) in rats are considered a potent developmental model of schizophrenia.

After NVHL, rats appear normal during their preadolescent time, whereas in early adulthood, they develop behavioral deficits paralleling symptomatic aspects of schizophrenia, including hyperactivity, hypersensitivity to amphetamine (AMPH), prepulse and latent inhibition deficits, reduced social interactions, and spatial working and reference memory alterations.

Surprisingly, the question of the consequences of NVHL on postnatal neurobehavioral development has not been addressed. This is of particular importance, as a defective neurobehavioral development could contribute to impairments seen in adult rats.

Therefore, at several time points of the early postsurgical life of NVHL rats, we assessed behaviors accounting for neurobehavioral development, including negative geotaxis and grip strength (PD11), locomotor coordination (PD21), and open-field (PD25).

At adulthood, the rats were tested for anxiety levels, locomotor activity, as well as spatial reference memory performance.

Using a novel task, we also investigated the consequences of the lesions on procedural-like memory, which had never been tested following NVHL.

Our results point to preserved neurobehavioral development. They also confirm the already documented locomotor hyperactivity, spatial reference memory impairment, and hyperresponsiveness to AMPH.

Finally, they show for the first time that NVHL disabled the development of behavioral routines, suggesting dramatic procedural memory deficits.

The presence of procedural memory deficits in adult rats subjected to NHVL suggests that the lesions lead to a wider range of cognitive deficits than previously shown. Interestingly, procedural or implicit memory impairments have also been reported in schizophrenic patients.

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