Hippocampus volume

Fluman studies seem to support the animal data on the role of neurotrophic factors in stress states. Depression appears to be associated with a drop in BDNF levels in the cerebrospinal fluid and serum as well as with a decrease in tyrosine kinase receptor activity. Conversely, administration of antidepressants increases BDNF levels in clinical trials and may be associated with an increase in hippocampus volume in some patients. 

In animals, the hippocampus is among the phylogenetically oldest parts of the brain. It occupies most of the ventroposte-rior and ventrolateral walls of the cerebral cortex in rodents. However, the hippocampus occupies less of the telencephalon in proportion to cerebral cortex in primates, especially in humans. The significant development of hippocampus volume in primates correlates with overall increase of brain mass and neocortical development. 

Rat (Wistar) 3 wk 7 d/wk ad lib (W) 15 (increase in volume of mossy fiber zone, granule cell layer, and commissural association zone in hippocampus of offspring) Slomianka et al. 1989 PbAc... 

Responses in the dopamine system are more complex (see chapter by Balfour, this volume). Repeated nicotine injections resulted in enhanced extracellular DA levels in the NAc (Benwell and Balfour 1992, 1997), but not in the striatum (Benwell and Balfour 1997). Analysis of the precise placement of dialysis probes has revealed differential responses to drugs of abuse, including nicotine, between the NAc core (ventral striatum) and shell (Di Chiara 2002 Balfour 2004 Wonnacott et al. 2005 see chapter by Balfour, this volume). Moreover, the sensitised neurotransmitter responses observed in the hippocampus and NAc were markedly attenuated if rats received a constant infusion of a low level of nicotine (Benwell and Balfour 1997). Thus, transient peaks of nicotine appear capable of sensitising some brain pathways with respect to catecholamine release, but the responses may be mitigated by lower sustained plasma concentrations, possibly due to desensitisation. The extent that presynaptic nAChRs contribute to this process in vivo is unclear presynaptic a7 nAChRs on glutamatergic afferents to the VTA merit attention as potential mediators of sensitisation (see Sect. 2.2.2). 

Current theories suggest that hypersecretion of cortisol during stress may damage the hippocampus. Studies have demonstrated reduced hippocampal volume in trauma survivors with PTSD, compared to nontrauma tized individuals (Sapolsky, 2000 Bremner, 2001). However, hormonally regulated plasticity in the hippocampus involves multiple influences, and glucocorticoid hormones work in concert with excitatory amino acids and N-methyl-D-aspartate (NMDA) receptors, as well as other neurotransmitters and the GABA-benzodiazepine system (see McEwen, 2000a,b, for review). 

Morphometric magnetic resonance imaging (MRI) studies provide further support for the concept of a subtle developmental brain anomaly. Szeszko et al. (1999) noted that OCD patients had reduced orbito-frontal and amygdala volumes bilaterally, and absence of the normal hemispheric asymmetry of the hippocampus-amygdala complex. Morphometric measurements of the basal ganglia also reveal decreased caudate size (Robinson et al., 1995 Jenike et al., 1996). 

Over 30 structural imaging studies suggest that major depression is associated with a 5-10% loss of volume in the hippocampus, although some studies have not replicated this finding. Depression and chronic stress states have also been associated with a substantial loss of volume in the anterior cingulate and medial orbital frontal cortex. Loss of volume in structures such as the hippocampus also appears to increase as a function of the duration of illness and the amount of time that the depression remains untreated. 

Exposure to silver has been observed to affect the volume of hippocampal cell groups within the brain of animals. Several cell groups within the hippocampus (a well defined structure of the brain involved in some aspects of memory) are reduced in overall volume in rats exposed during their first 4 weeks of life to subcutaneously injected silver lactate (0.137 mg silver/kg/day) (Rungby et al. 1987). Unfortunately, the study is limited in that only one small region of the brain was examined. It is prudent to assume that similar effects would be observed in humans however, the implications of the altered volume of these cell groups are not known. 

Silver has been demonstrated in the brains of neonatal rats whose mothers received injections of silver lactate on days 18 and 19 of gestation (Rungby and Danscher 1984). As mentioned above, treatment of neonatal rats has also been found to reduce the volumes of certain cell groups within the hippocampus (Rungby et al. 1987). However, functional tests were not performed on these rats, and therefore, neither the significance of the silver accumulation, nor the decrease in regional hippocampal volume can be determined. 

Rungby J, Slomianka L, Danscher G, et al. 1987. A quantitative evaluation of the neurotoxic effect of silver on the volumes of the components of the developing rat hippocampus. Toxicology 43 261-268. 

Here, we review the abnormalities of hippocampal structure and function in schizophrenia and consider how they can give rise to memory deficits and psychotic symptoms. While it is unlikely that the hippocampus is the sole locus of pathology in schizophrenia, there is now compelling evidence that (1) hippocampal volume and shape are abnormal early on in the disease process, (2) specific regions of the hippocampus show alterations of neuronal gene expression, protein expression, and cell number, and (3) cognitive deficits and the experience of psychotic symptoms are linked to abnormalities of hippocampal function. 

The initial evidence for abnormalities of the hippocampus in schizophrenia came from postmortem and structural imaging studies. A study exploring volume changes in limbic brain regions reported... 

The hippocampus is not smaller in all patients with schizophrenia, i.e., hippocampal volume alone is not a biological marker and cannot be used to make the diagnosis of schizophrenia. Furthermore, several other diseases, most notably unipolar depression (Campbell and Macqueen, 2004), PTSD (Smith, 2005), and alcoholism (Geuze et al., 2005) are also associated with reduced hippocampal volume. Does smaller hippocampal volume tell us something about a unique pathology in schizophrenia or is hippocampal volume decrease the final common pathway of several pathological conditions ... 

Despite the considerable evidence reviewed above, the significance of smaller hippocampal volume in schizophrenia remains unclear. Under the best of circumstances, hippocampal volume studies will help to diagnose schizophrenia (Davatzikos et al., 2005) and will have predictive power for illness progression and outcome. Additional information about the chemical constituents of the hippocampus, e.g., those measured by proton spectroscopy (Steen et al., 2005), could help to clarify the underlying pathological process. However, it is clear already now that a more detailed analysis of the hippocampus at the level of cellular organization and molecular mechanisms is required to appreciate fully a potential role of the hippocampus in schizophrenia. 

Is there any evidence for deficits in subsets of hippocampal neurons Here, we will briefly review the evidence for an abnormality of the GABAergic and glutamatergic neurons in the hippocampus in schizophrenia (reviewed by others (Benes, 1999 Arnold, 2000 Benes and Berretta, 2001 Harrison and Eastwood, 2001 Harrison, 2004) and in this volume (Kristiansen et al.)). 

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