Cholecystokinin-immunoreactive boutons in synaptic contact with hippocampal pyramidal neurons that project to the nucleus accumbens

doi:10.1016/0306-4522(86)90014-X

Neuroscience

Volume 19, Issue 1, September 1986, Pages 181-192

https://doi.org/10.1016/0306-4522(86)90014-X Get rights and content

Abstract

Neurons in the hippocampal formation of the rat that project to the medial nucleus accumbens were identified following the retrograde transport of a conjugate of horseradish peroxidase with wheat germ agglutinin. The great majority of such projecting neurons were located in the ventral subiculum and were pyramidal in shape; the pyramidal nature of 25 such retrogradely labelled neurons was established by Golgi impregnation. In material processed to reveal both retrogradely labelled cells and cholecystokinin-immunoreactivity, no immunoreactive projecting neurons were found. However, 48 identified projecting neurons, probably pyramidal, were found to receive input from cholecystokinin-immunoreactive boutons that formed symmetrical synaptic contacts with the soma or proximal dendrites.

It is suggested that one function of cholecystokinin-immunoreactive neurons in the hippocampal formation might be to influence the output of the pyramidal neurons that project to the nucleus accumbens. Since this pathway is one of the main links between the limbic system and the basal ganglia, it is conceivable that changes in the cholecystokinin levels in the hippocampus, as found in schizophrenia, might influence behaviour through the pathway connecting the hippocampus with the nucleus accumbens.

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Activation of the retrohippocampal region in the rat causes dopamine release in the nucleus accumbens: Disruption by fornix section
2000, European Journal of Pharmacology
There is a well-described projection from the retrohippocampus (subiculum and entorhinal cortex) to the nucleus accumbens that is involved in the control of psychomotor behaviour, and is implicated in the aetiology of schizophrenia. Cortical abnormalities are widely reported in the brains of schizophrenic patients, but it is unclear whether they are the cause or consequence of those changes in subcortical systems that are treated with neuroleptic drugs. We have, therefore, conducted a series of microdialysis experiments in anaesthetized rats to determine whether infusion of the excitotoxin, N-methyl-d-aspartate, into the retrohippocampus increases mesolimbic dopamine release. We found a clear and reproducible increase in extracellular dopamine in the nucleus accumbens following N-methyl-d-aspartate (2.5 μg), that was abolished when we sectioned the fimbria-fornix. Furthermore, inhibition of γ-aminobutyric acid receptors following retrohippocampus administration of bicuculline (4 μg), also increased dopamine in the nucleus accumbens. The dopamine response to bicuculline was accompanied by an increase in dopamine metabolism, was long lasting, and also reduced by fornix section.
The response to both N-methyl-d-aspartate and bicuculline depends on the integrity of the projection from the retrohippocampus to the nucleus accumbens. The results provide an underlying mechanism whereby a primary insult in the temporal cortex, caused by excessive N-methyl-d-aspartate receptor stimulation, can produce a hyperdopaminergic state. In addition, an increase in subiculo-accumbens activity evoked by bicuculline may also explain why patients with limbic epilepsy can develop a psychosis.
Effects of antipsychotic drugs on cholecystokinin and preprotachykinin (substance P) mRNA expression in the rat hippocampal formation
2000, European Neuropsychopharmacology
To assess the involvement of substance P (SP) and cholecystokinin (CCK) in the effects of antipsychotic drugs, preprotachykinin-A (PPT-A) and CCK mRNA expression was studied in the hippocampal formation using in situ hybridisation following 21 daily i.p. injections with the typical antipsychotic drug haloperidol (1 mg/kg) and the atypical drug clozapine (15 mg/kg). PPT-A mRNA levels were increased in the hippocampal CA3 subregion and in the entorhinal cortex after haloperidol, whereas a decrease was observed in the CA1 after clozapine. CCK mRNA levels increased in the CA1, the entorhinal cortex and in hilus, following both haloperidol and clozapine. It is suggested that earlier findings of increased SP levels in the hippocampal formation of schizophrenics may be a consequence of haloperidol treatment and that reduced hippocampal CCK and CCK mRNA levels found earlier in schizophrenics do not result from antipsychotic drug treatment. These results are consonant to the hypothesis that increased cortical CCK transmission may be beneficial in the treatment of psychosis.
Abnormal cholecystokinin mRNA levels in entorhinal cortex of schizophrenics
1997, Journal of Psychiatric Research
Limbic cortical regions, including anterior cingulate cortex (ACC), prefrontal cortex (PFC) and entorhinal cortex (ERC), have been implicated in the neuropathology of schizophrenia. Glutamate projection neurons connect these limbic cortical regions to each other, as well as to the terminal fields of the striatal/accumbens dopamine neurons. Subsets of these glutamate projection neurons, and of the GABA interneurons in cortex, contain the neuropeptide cholecystokinin (CCK). In an effort to study the limbic cortical glutamate projection neurons and GABA interneurons in schizophrenia, we have measured CCK mRNA with in situ hybridization histochemistry in postmortem samples of dorsolateral (DL)PFC, ACC and ERC of seven schizophrenics, nine nonpsychotic suicides and seven normal controls. CCK mRNA is decreased in ERC (especially layers iii–vi) and subiculum in schizophrenics relative to controls. Cellular analysis indicates that there is a decrease in density of CCK mRNA in labelled neurons. In so far as ERC CCK mRNA is not reduced in rats treated chronically with haloperidol, this decrease in schizophrenics does not appear to be related to neuroleptic treatment. In contrast, in DLPFC, where schizophrenics do not differ from normals, the suicide victims have elevated CCK mRNA (especially in layers v and vi), and increased cellular density of CCK mRNA, relative to both normals and schizophrenics. These results lend further support for the involvement of ERC and hippocampus in schizophrenia, suggesting that neurons that utilize CCK may be particularly important. Similarly, an increase in CCK mRNA levels in the PFC of suicides adds to a growing body of evidence implicating this structure in this pathological state. In so far as CCK is co-localized with GABA or glutamate in cortical neurons, both of these neuronal populations need to be studied further in schizophrenia and suicide.
Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia
1995, Neuroscience
It has been proposed that synaptic density or synaptic innervation may be altered in schizophrenia as a correlate of the neurodevelopmental pathology of the disease. Synaptophysin is a synaptic vesicle protein whose distribution and abundance provides a synaptic marker which can be reliably measured in post mortem brain. We have used in situ hybridization histochemistry and immunoreactivity to assess the expression of synaptophysin messenger RNA and protein respectively in medial temporal lobe from seven schizophrenics and 13 controls.
In the schizophrenic cases, synaptophysin messenger RNA was reduced bilaterally in CA4, CA3, subiculum and parahippocampal gyrus, with a similar trend in dentate gyrus but no change in CA1. It was also decreased in terms of grains per pyramidal neuron in the affected subfields. In parahippocampal gyrus, the loss of synaptophysin messenger RNA per neuron in schizophrenia was greater in deep than superficial laminae. A parallel study in rats showed no effect of haloperidol treatment upon hippocampal synaptophysin messenger RNA, suggesting that neuroleptic treatment does not underlie the reductions found in schizophrenia. In the right medial temporal lobe of schizophrenics, we confirmed the correlations of synaptophysin messenger RNA abundance between ipsilateral subfields seen in both hemispheres of control brains. However, these correlations were not observed in the left medial temporal lobe of the schizophrenic cases. Synaptophysin immunoreactivity in schizophrenia showed no significant differences in any subfield compared to controls.
Our data support the broad hypothesis that synaptic pathology occurs in schizophrenia. In so far as synaptophysin expression is a marker for synaptic density, the data suggest that pyramidal neurons within the medial temporal lobe may form fewer synapses. However, the lack of any significant differences in synaptophysin immunoreactivity despite the loss of encoding messenger RNA means that this conclusion must be drawn cautiously. There are several plausible explanations for the preservation of synaptophysin immunoreactivity despite reductions in transcript abundance; one possibility is that the inferred loss of synapses occurs in extra-hippocampal sites to which the affected pyramidal neurons project. For example, the reduction in synaptophysin messenger RNA in subicular neurons may be accompanied by decreased density of synaptic terminals in the nucleus accumbens. Such differences in the efferent synaptic connectivity of the hippocampus have previously been hypothesized to be an important component of the circuitry underlying schizophrenia.
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1994, Neuroscience
Both tyrosine hydroxylase-positive fibres from the mesolimbic dopamine system and amygdala projection fibres from the basolateral nucleus are known to terminate heavily in the nucleus accumbens. Caudal amygdala fibres travelling dorsally via the stria terminalis project densely to the nucleus accumbens shell, especially in the dopamine rich septal hook. The amygdala has been associated with the recognition of emotionally relevant stimuli while the mesolimbic dopamine system is implicated with reward mechanisms. There is behavioural and electrophysiological evidence that the amygdala input to the nucleus accumbens is modulated by the mesolimbic dopamine input, but it is not known how these pathways interact anatomically within the nucleus accumbens. Using a variety of neuroanatomical techniques including anterograde and retrograde tracing, immunocytochemistry and intracellular filling, we have demonstrated convergence of these inputs on to medium-sized spiny neurons. The terminals of the basolateral amygdala projection make asymmetrical synapses predominantly on the heads of spines which also receive on their necks or adjacent dendrites, symmetrical synaptic input from the mesolimbic dopamine system. Some of these neurons have also been identified as projection neurons, possibly to the ventral pallidum.
We have shown a synaptic level how dopamine is positioned to modulate excitatory limbic input in the nucleus accumbens.
Spatial, movement- and reward-sensitive discharge by medial ventral striatum neurons of rats
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Cholecystokinin-immunoreactive boutons in synaptic contact with hippocampal pyramidal neurons that project to the nucleus accumbens

Abstract

Brain Res.

Neurosci. Lett.

Neuropeptides

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Neurosci. Lett.

Neurochem. Int.

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Peptides

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Microiontophoretic studies of the dopaminergic inhibition from the ventral tegmental area to the nucleus accumbens neurons

J. Pharmac. exp. Ther.

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Brain

Antispsychotic drug effects on the electrical activity of dopaminergic neurons

The organisation of cortico-striate connections in the rabbit

Brain

The organization of nucleus accumbens

The projection field of the stria terminalis in the rat brain. An experimental study

J. comp. Neurol.