With bilateral hippocampus damage memory of what has just happened is lost. The subjects do not develop schizophrenia.
The baseline activity of dopaminergic neurons in the Ventral Tegmental Area in the midbrain [ VTA ] are regulated by the ventral hippocampus,
disruptions in dopamine signalling associated with schizophrenia
may be caused by the hippocampal abnormalities reported in the disease.
One hippocampal area stood out: the CA1 subfield of the hippocampus.
The findings suggest that, in schizophrenia, oxygen use increases in the hippocampal CA1 subfield, and the orbitofrontal cortex.
In contrast, it seems to decrease in the dorsolateral prefrontal cortex.
18 prodromal subjects were studied who met clinical criteria for being at ultra high risk of developing psychosis.
These subjects presented symptoms that did not quite rise to the level seen in psychosis.
For example, prodromal subjects might profess unusual ideas that seem less compelling than delusions.
During the two years of follow-up, seven of the prodromal subjects became psychotic. Of the three dysfunctional areas seen in subjects with more established disease, only the CA1 subfield appeared awry in these subjects.
Notably, high activity in this area predicted the eventual emergence of psychosis.
In fact, it did so with a positive predictive value of 71 percent and a negative predictive value of 82 percent.
Not only do these findings yield insight into the earliest stages of psychosis, they raise hopes for a marker to flag those at greatest risk with the idea of someday preventing the disease from taking its toll.
The hope from this is that the dopamine surge at onset is something that dopamine blocking medication, applied early, can now be be tested to see if what here is shown to be a forerunner of florid schizophrenia can be halted .
[ The illnesss progression may be cut short, and more residual functioning allowed to go on at a better level towards normality. ]
go to memory studies
In this article
Grace and colleagues develop the concept that the hippocampus and the midbrain dopaminergic neurons
of the ventral tegmental area ( VTA) form a functional loop.
Activation of the loop begins when the hippocampus detects newly arrived information
that is not already stored in its long-term memory. The resulting novelty signal is conveyed through the subiculum, accumbens,
and ventral pallidum to the VTA where it contributes (along with salience and goal information)
to the novelty-dependent firing of these cells.
In the upward arm of the loop, dopamine (DA) is released within the hippocampus; this produces an enhancement of LTP and learning.
These findings support a model whereby the hippocampal-VTA loop regulates the entry of information into long-term memory.
One of the most important brain regions involved in discovering, processing and storing new sensory impressions
is the hippocampus, located in the temporal lobe of the cerebral cortex.
Novel stimuli tend to activate the hippocampus more than familiar stimuli do,
which is why the hippocampus serves as the brain's novelty detector."
The hippocampus compares incoming sensory information with stored knowledge.
If these differ, the hippocampus sends a pulse of the messenger substance dopamine to the substantia nigra (SN) and ventral tegmental area (VTA) in the midbrain.
From there nerve fibers extend back to the hippocampus and trigger the release of more dopamine.
Researchers, including John Lisman of Brandeis University and Anthony Grace of the University of Pittsburgh, call this feedback mechanism the hippocampal-SN/VTA loop
This feedback loop is why we remember things better in the context of novelty.
As Shaomin Li and his colleagues at Trinity College Dublin discovered in 2003,
the release of dopamine in the hippocampus of rats activates the synapses among target nerve cells,
creating stronger connections that lead to long-term memory storage.
They wondered whether this same neuronal loop facilitates the retention of other information that is perceived along with novel stimuli.
Functional magnetic resonance imaging measures the activity of various brain regions based on blood flow.
We presented one group of test subjects with a set of already known images
and a second group with a combination of known and new images.
Subjects in the second group were better at remembering the images than subjects in the first group were,
and the fMRI data showed greater activity in the SN and VTA areas of the brain
when the subjects were viewing unfamiliar images.
This correlation may help explain how novelty improves memory.
Increased Retention
Are the effects of novelty on memory merely temporary?
To answer this question, we showed test subjects a variety of photographs
and measured their brain activity using fMRI.
We also gave the participants a series of words to sort according to their meaning.
The experiment continued the next day when we showed some of the test subjects new images while others viewed familiar ones.
Then we asked all the subjects to recall as many words from the previous day's exercise as they could.
Recall was significantly better in the group that had just viewed new images.
In other words, novelty seems to promote memory.
This finding gives teachers a potential tool for structuring their lessons more effectively. Although most teachers start a lesson by going over material from the previous class before moving on to new subject matter, they should probably do just the opposite: start with surprising new information and then review the older material.
Grace and GOTO
Information gleaned from learning and memory processes is essential in guiding behavior toward a specific goal.
However, the neural mechanisms that determine how these processes are effectively utilized to guide goal-directed behavior are unknown.
Here, we show that rats utilize retrospective and prospective memory
and flexible switching between these 2 memory processes to guide behaviors to obtain rewards.
We found that retrospective memory is mainly processed in the hippocampus (HPC)
but that this retrospective information must be incorporated within the prefrontal cortex (PFC)
to be used to switch to an anticipatory response strategy involving prospective memory.
Furthermore, switching between memory processes is regulated by the mesocortical dopamine (DA) system.
Thus, DA D1 and D2 receptor activation in the PFC differentially
affects retrospective memory processing within the HPC via an indirect feedback pathway.
In contrast, D1, but not D2, receptor activation is crucial for incorporation of HPC-based retrospective information into the PFC.
However, once this takes place, D2 receptor activation is required for further processing of information to effect preparation of future actions.
These results provide a unique perspective on the mechanism of memory-based goal-directed behavior.
hippo new cells
Given the primary mechanism of action of psychostimulants is to enhance extracellular DA, it is not surprising that there is considerable evidence demonstrating that behavioral sensitization is attributable, at least in part, to enhanced activity of the mesolimbic DA pathway
The activity of the mesolimbic DA system is regulated via two independent mechanisms: -
1) transient or "phasic" DA release that is mediated mainly through DA neuron burst firing,
and 2)
extrasynaptic or "tonic" levels of DA that are mediated by basal DA neuron activity and regulated via presynaptic inputs
Thus it has been demonstrated that DA neuron burst firing induces a large transient increase in synaptic DA in target regions
and is considered to be the temporally relevant signal sent to postsynaptic sites to encode reward prediction or indicate incentive-salience
In contrast, tonic DA transmission occurs over a much slower time scale
and has been proposed to regulate the responsivity of the DA system through pre- and post-synaptic mechanisms
One region that potently modulates DA neuron activity is the ventral hippocampus,
a temporal lobe structure involved in memory formation
as well as the processing of novel and contextual information .
vHipp activation increases DA neuron population activity (i.e., number of DA neurons firing spontaneously)
that is correlated with significant increases in extracellular DA levels in the nucleus accumbens (Acb)
Furthermore, the hippocampus itself receives a significant input from the VTA and it has been demonstrated that DA acts to modulate hippocampal plasticity and subsequently learning and memory
Thus, long-term potentiation (LTP), an index of synaptic strength and prominent form of signaling in the hippocampus, is strongly dependent on DA.
More specifically, late-phase LTP is blocked by dopamine D1 receptor antagonists and is absent in D1 receptor knockout mice
whereas D1 receptor activation leads to an enhancement of hippocampal LTP
The augmented responsivity to psychomotor stimulants observed in amphetamine-sensitized rats is likely attributable
to an increase in tonic DA transmission secondary to augmented activity within the ventral hippocampal.
Moreover, an augmentation of vHipp drive was also found in an animal developmental model of schizophrenia,
in which endogenous vHipp overdrive also leads to aberrant DA signaling
The nucleus accumbens (NAc) is an integral part of limbic circuits proposed to play a central role in the pathophysiology of schizophrenia,
and is positioned to integrate information from limbic and cortical regions, including the medial prefrontal cortex (mPFC) and the hippocampus.
The ventral subiculum (vSub) of the hippocampus, in particular, is proposed to gate information flow within the NAc,
a factor that is disrupted in models of schizophrenia.
Using in vivo extracellular recordings in anesthetized rats,
we examined the response of NAc neurons to vSub stimulation and how this is modulated by the mPFC.
We found that inactivation of mPFC by tetrodotoxin attenuates the ability of the vSub to drive spike firing in the NAc.
Thus, a contribution of the mPFC is required for the activation of NAc by the vSub.
However, when long-term potentiation is induced in the vSub-NAc pathway,
the vSub is now capable of driving the NAc without the participation of the mPFC.
Moreover, this interaction is dependent on activation of dopaminergic D2 receptors in the NAc.
This work demonstrates the critical role of the mPFC in the ability of vSub to drive NAc neurons in normal anesthetized animals.
One model of schizophrenia posits that vSub hyperactivity may underlie both the hyperdopaminergic state and disruption of information flow in this circuit in schizophrenia.
oligodendrocytes
Scottish scientists have discovered a gene which may help explain the causes of mental illness.
Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of ?80% indicating a substantial genetic component.
Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses
but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations.
We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder.
After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls.
Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases.
Variants were genotyped in additional schizophrenia, bipolar, depression (n 1600), and control (n 950) cohorts and the frequency of all rare variants combined
was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives
and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression.
These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression
, and suggest that rare coding variants may contribute significantly to risk of these disorders.
studying a genetic locus for bipolar disorder on human chromosome 4p investigators
The ABCA13 gene is partially inactive in patients with severe psychological conditions
such as schizophrenia, bipolar disorder and depression.
This study is published in the August 15 printed issue of Proceedings of National Academy of Sciences.
The team believes the gene may influence the way fat molecules are used in brain cells and the research will now focus on exactly how this occurs.
This study is the first to identify multiple points of DNA damage within a single gene that are linked with psychiatric illness.
"It strongly suggests that this gene may regulate an important part of brain function
that fails in individuals diagnosed with these devastating disorders.
Earlier research [at Mount Sinai and elsewhere] suggests that schizophrenia is associated with changes in myelin,
the fatty substance or white matter in the brain that coats nerve fibers and is critical for the brain to function properly.
Myelin is formed by a group of central nervous cells called oligodendrocytes,
which are regulated by the gene oligodendrocyte lineage transcription factor 2 (OLIG2).
Patients with schizophrenia are known to have insufficient levels of oligodendrocytes, however the source of this [deficiency] has not been identified,
explains study co-author Joseph D. Buxbaum,
The study showed that genetic variation in OLIG2 was strongly associated with schizophrenia.
In addition, OLIG2 also showed a genetic association with schizophrenia
when examined together with two other genes previously associated with schizophrenia-
-CNP and ERBB4--which are also active in the development of myelin.
The expression of these three genes was also coordinated. Taken together the data support an etiological role for oligodendrocyte abnormalities in the development of schizophrenia.
Dr. Buxbaum and a team of Mount Sinai researchers collaborated with researchers from the Cardiff University School of Medicine in the United Kingdom
to analyze DNA in blood samples taken from 673 unrelated patients with schizophrenia
and compared their genetic information to 716 patients who did not have the disease.
The controls were matched for age, sex, and ethnicity; none were taking medications at the time of the study.
The study showed that genetic variation in OLIG2 was strongly associated with schizophrenia. In addition, OLIG2 also showed a genetic association with schizophrenia when examined together with two other genes previously associated with schizophrenia--CNP and ERBB4--which are also active in the development of myelin. The expression of these three genes was also co-ordinated. Taken together the data support an etiological role for oligodendrocyte abnormalities in the development of schizophrenia.
The study showed that genetic variation in OLIG2 was strongly associated with schizophrenia.
In addition, OLIG2 also showed a genetic association with schizophrenia
when examined together with two other genes previously associated with schizophrenia--CNP and ERBB4-
-which are also active in the development of myelin.
The expression of these three genes was also coordinated.
Taken together the data support an etiological role for oligodendrocyte abnormalities in the development of schizophrenia.
"Multiple genes likely have a role in schizophrenia and there are probably many things happening in the brain of a schizophrenia patient," Dr. Buxbaum says.
"The findings from this study help us tease out a potential biological cause that may be contributing to this debilitating illness.
This study showed that OLIG2 has a causal etiological effect
and these findings give us a stronger sense of where to look so we can develop more therapeutic targets for this very complex disease."
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Three memory studies in schizophrenia