Anatomic Networks

Amygdalo-Cingulo-Hippocampal Circuitry and Stress

In 1878, Broca [231] designated a rim-like confluence of cortex along the mid-sagittal surface of mammalian brain as the limbic lobe. Comprised primarily of the cingulate gyrus, hippocampal formation and amygdala, the limbic lobe has shown remarkable conservation during the phylogenesis of mammalian brain. Based on this observation, Broca postulated that these structures might be of central importance to the processing of the emotional components of cognitive behaviour. More recently, MacLean [232] extended this concept by suggesting that emotional disorders, such as schizophrenia, might involve abnormalities in the organization and functioning of the extended limbic system.

The amygdala is a particularly important cortico-limbic region that lies at the anterior tip of the temporal lobe. Considered by some to be an "arbitrarily defined set of cell groups", there are nevertheless subdivisions of this region that can be distinguished by their characteristic architecture, embryogenesis, neurotransmitter profiles, connectivity and functional roles. These include an olfactory part (central and main) that projects topographically to other regions involved in reproductive, defensive and ingestive behaviour systems in the hypothalamus, a central nucleus that projects to autonomic centres in the brainstem, and the fronto-temporal system that projects to the striatum, nucleus accumbens, hippocampus and cortex. The latter system is distinguished from the other more "primitive" components of the amygdala by its being a ventral extension of the claustrum; because of this, it is considered to be a derivative of frontal and temporal cortex. While the central subdivisions of the amygdala have projection neurons that employ GABA as a neurotransmitter, thus establishing their homology with the basal ganglia, the projection neurons of the basolateral complex, like those of the cortex, use glutamate as a transmitter.

The hippocampal formation plays a central role in the retrieval of information from memory storage [233-235]. Recent PET studies have examined the response of the hippocampus to episodic memory retrieval [71] in patients with schizophrenia and demonstrated that basal metabolic activity is increased in the hippocampus at rest. The patients in this study showed a significantly higher basal metabolic rate in the hippocampal formation. Under the conditions of low recall, however, there was no change in cerebral blood flow to the hippocampus, while under high recall conditions there was a slight decrease. The fact that the baseline was much higher than in normal subjects suggests the possibility that a "ceiling effect" might have occurred in the subjects included in this study. An alternative possibility, however, is that the hippocampus of schizophrenics may have a disturbance in the relay of information along the trisynaptic pathway, one that belies the overall increase of activity detected under baseline conditions.

Stress appears to play a central role in modulating the activity of both the amygdala [236] and the hippocampus [237]. The basolateral nucleus of the amygdala influences memory-modulating systems in relation to emotionally arousing events (for a review, see [210]). Both norepinephrine and dopamine show an increased release in the amygdala of stressed animals. For the dopamine system, acute stress is associated with a selective increase in the release of this transmitter from the ACC, also known as the medial prefrontal cortex in rodents [238, 239].

The connections between the amygdaloid complex and the ACC may be particularly important to understanding the pathophysiology of neuropsy-chiatric disorders. Layer II of the anterior cingulate region, where a variety of anomalies have been detected in schizophrenia (see above), receives a "massive" input from the basolateral complex of the amygdala [240]. In a series of post-mortem studies, an increase of vertical fibres was found in layer II of the ACC and the entorhinal region, but not the prefrontal cortex (for a review, see [241]). Since this latter region does not receive an appreciable input from the amygdala, it seemed possible that those fibres showing an increase in the anterior cingulate area might originate in a region, like the amygdala, that projects to the cingulate cortex, but not the prefrontal area [240]. Although post-mortem studies cannot establish a direct link between these two neuronal compartments, it seems likely that the basolat-eral nucleus and the anterior cingulate region may play an important role in the pathophysiology of schizophrenia and other neuropsychiatric disorders.

Cortico-Striato-Thalamo-Cortical Loops and Central Filtering

Neuroanatomists have known for some time that there is a continuous loop of connections between the cortex, striatum and thalamus. Since the dopa-

mine projections to the striatum are arguably the most abundant ones in the brain, Carlsson et al. [242] have postulated that this neuromodulator contributes significantly to the pathophysiology of psychosis and its treatment with neuroleptic drugs via the cortico-striato-thalamo-cortical loop. Notable features of this model include descending glutamatergic projections from the cortex that exert an excitatory influence over GABAergic projection cells in the striatum [243]. This circuitry involves GABA-to-GABA projection pathways between the striatum and globus pallidus that inevitably result in disinhibitory effects converging on the thalamus. Such a mechanism would tend to reduce the filtering of sensory information passing through the thalamus to the cortex, although there are also parallel relays that would result in an overall increase of inhibitory inputs and therefore filtering activity in the thalamus. PPI is thought to involve the nucleus accumbens, a ventral subdivision of the corpus striatum [205], suggesting that more limbic components of the basal ganglia may be the more precise components of this circuitry involved in schizophrenia. In any case, the cortico-striato-thalamo-cortical loop is a very complex circuit that offers a multitude of mechanisms as possible drug targets in schizophrenia.

THE NEURODEVELOPMENTAL HYPOTHESIS Disturbances of Cell Migration

The findings of a variety of changes in layer II of the anterior cingulate and prefrontal cortices suggested the possibility that there might be a disturbance in the migration of neurons in the developing cortex of subjects with schizophrenia [244]. To investigate this possibility further, the distribution of nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase was examined in the prefrontal cortex of normal controls and schizophrenics [93]. The results demonstrated a significantly higher density of cells showing this marker in the subcortical white matter than in the cortical mantle [245]. Of significance to the current discussion is the fact that NADPH diaphorase has been co-localized to subpopulations of interneurons that are GABAergic in nature [246-254].

Reelin and Cortical Lamination

Another line of investigation that has pointed to a possible neurodevelop-mental mechanism playing a role in the pathophysiology of schizophrenia has come from studies of reelin, a protein extracted from the Reeler mouse mutant. Reelin is believed to be secreted by a subclass of interneurons called

Cajal-Retzius cells that may be GABAergic in nature [255, 256]. These neurons are the first to appear and are localized in layer I [257]. During early development of the cortex, they interact with Martinotti cells in deeper laminae and may play a role in the formation of laminar patterns [257]. In both schizophrenia and bipolar disorder, reelin and GAD67 mRNA have been found to be decreased in layer I and, to a lesser extent, layer II [152]. These latter findings are consistent with both a cell counting study [86] and highresolution analyses of GABAA receptor binding activity [169] showing preferential changes in layer II of the prefrontal cortex. The authors of these studies propose that a down-regulation of reelin expression in this region of schizophrenic and bipolar brain may be due to either a genetic or an epigenetic factor. Since this protein is reduced in both schizophrenia and bipolar disorder, it seems more likely that the changes noted might be related to an environmental factor common to both. In this regard, it is noteworthy that obstetrical complications have been found to occur in both schizophrenia [49] and bipolar disorder [51, 57], making it plausible that an insult early in life could influence the expression of this protein during adulthood.

Postnatal Ingrowth of Extrinsic Afferents

Important questions regarding the role of a neurodevelopmental disturbance in the induction of altered phenotypes of GABA cells are when and how such changes become manifest during the life cycle in individuals who carry the susceptibility genes for schizophrenia and bipolar disorder. One possibility is that the GABA cells are abnormal from birth; however, the clinical observation that most subjects with schizophrenia are relatively normal during childhood and early adolescence argues against this possibility. It is important to emphasize, however, that studies in rat suggest that the cortical GABA system continues to develop until the equivalent of early adolescence [258-262]. Taking these observations together, a second possibility is that the GABA cells are relatively normal during childhood when they are also relatively immature, but become abnormal as their maturation process is completed. A vulnerability gene or genes associated with schizophrenia or bipolar disorder could initiate such a change. In this latter case, it would be assumed that both disorders would share common genes and these would be capable of altering the normal functioning of GABA cells. A third possibility is that the GABA cells are either relatively normal or abnormal during childhood, but their activity is quiescent as they await the ingrowth of an extrinsic fibre system, such as the dopaminergic afferents to the medial prefrontal cortex [263, 264]. These latter fibres continue forming increased numbers of appositions with GABAergic interneurons until the early adult period [265].

Influence of Pre- and Postnatal Stress

The role of stress in the induction of changes in the cortical GABA system in schizophrenia and bipolar disorder is an interesting issue to explore. For example, glucocorticoid hormones have the ability to bind to the GABAa receptor [266] and have been found to directly increase its activity [267, 268]. In this regard, it is noteworthy that the binding of [3H]corticosterone is greatest in sector CA2 [269, 270], where schizophrenics and bipolars both show a marked decrease of non-pyramidal neurons and the largest increase of GABAA receptor binding (see above). It is important to point out, however, that stress is believed to increase rather than decrease the activity of the GABA system [272-274], although it is possible that chronic stress, particularly when preceded by stress in utero, might result in an eventual decrease in the activity of this transmitter system. This possibility is particularly intriguing when the marked sensitivity of GABAergic neurons to excitotoxic injury [275] is taken into account. It is believed that cell death in this setting probably requires both an increase of excitatory activity and an increased release of glucocorticoid hormone [276].

Another important component to the stress response is the increased release of dopamine that occurs in the medial prefrontal cortex [238, 239]. Relevant to this discussion is the fact that an increase of dopamine varicos-ities forming appositions with GABAergic interneurons has been induced by exposing rats both pre- and postnatally to stress-related doses of corti-costerone [87]. Thus, it is possible that the postnatal maturation of GABA cells in the cortex may be normally influenced by the ingrowth of dopamine fibres, but abnormally affected when this occurs in individuals for whom pre- and postnatal stress are comorbid factors. In this latter case, it would have to be assumed that any gene or genes involving the dopamine system and perhaps also cortical GABA cells would be affected by prenatal exposure to stress and would be permanently sensitized in such individuals.

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