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Rat Cingulate Cortex & Disease Models (3 of 3)

Figure 12. Circuitry mediating NRHypo toxicity. Glu acts via NMDA receptors on GABAergic and noradrenergic (NE) neurons and maintains tonic inhibitory control over two major excitatory pathways that innervate neurons in RSC (areas 29a-c). Systemic administration of NMDA antagonists block NMDA receptors and abolish inhibitory control over excitatory inputs to RSC. The disinhibited excitatory pathways hyper-activate RSC neurons, possibly disrupting multiple intracellular signaling systems, thereby causing immediate derangement of the cognitive functions of RSC and reversible or irreversible neuronal injury, depending upon the length of the exposure. It is postulated that the glutamatergic cell bodies that project to the AMPA/KA receptors in RSC are located in the anterior thalamus. Although this diagram emphasizes RSC, a similar disinhibitory mechanism and similar but not necessarily the same circuits and receptor mechanisms may mediate damage in other regions by sustained NRHypo. Excitatory (+) and inhibitory(-) inputs are shown. ACh, acetylcholine; GA, GABAA receptor; m3, muscarinic receptor (m3 subtype); s, sigma site; 5-HT, serotonin.

Non-NMDA glutamatergic system. While these data confirm that disinhibition of the cholinergic system is a necessary component underlying NRHypo neurotoxicity, it is not sufficient because the injection of carbachol, a muscarinic agonist, directly into the RSC does not reproduce the damage (Farber et al., 2002). NMDA antagonists also produce excessive release of Glu in the cerebral cortex suggesting that excessive stimulation of glutamatergic receptors might also be involved in the neurotoxic process. NBQX, an antagonist of AMPA and KA receptors, protects against NRHypo neurotoxicity, when applied systemically or when injected directly into the RSC (Farber et al., 2002), indicating that the excessively stimulated glutamatergic receptors are likely of the AMPA/KA subtype. Although injection of KA or AMPA directly into the RSC does not reproduce the damage (Farber et al., 2002), co-injection of KA and carbachol does reproduce the neurotoxicity (Farber et al., 2002). The need for both agents to produce the damage indicates that the combined excessive activation of both muscarinic and non-NMDA, glutamatergic receptors is necessary and sufficient to produce the neurotoxicity. Injection of muscimol into either the AD/AV or LD nucleus of the thalamus, where thalamic input into the RSC arises (Figs. 6 and 9), protects against NRHypo neurotoxicity (Jiang et al., 2001), indicating that thalamic glutamatergic neurons are the likely source of the excessive release of Glu in the RSC and that these neurons also are under tonic inhibition from NMDA-receptor bearing GABAergic neurons (Fig 12).

Additional evidence that NMDA antagonists produce disinhibition. Based on this disinhibition model, agents that reduce the ability of these excitatory projections to release excessive neurotransmitter and stimulate the vulnerable RSC neuron should protect against the neurotoxic reaction. Activation of voltage-gated sodium channels is necessary for propagation of the action potential down the axon and inhibitors of these channels, e.g. tetrodotoxin, valproic acid, and carbamazepine, prevent NRHypo neurotoxicity (Farber et al., 2002b). NMDA antagonists also acutely increase metabolism in certain corticolimbic regions (Farber et al., 1999, 2002). In general the corticolimbic regions experiencing hypermetabolism tend to be the same corticolimbic regions that also develop either the reversible or irreversible forms of NRHypo neurotoxicity. The increase in metabolism in these corresponding regions could be a reflection of a disinhibition syndrome in which acetylcholine and Glu are excessively released at certain corticolimbic neurons that are injured in the NRHypo neurotoxic syndrome. Consistent with this proposal, clozapine and halothane reverse the hypermetabolism induced by NMDA antagonists (Duncan et al., 1998b) just as they reverse NRHypo neurotoxicity (Ishimaru et al., 1995; Farber et al., 1996).

Other markers of NRHypo-induced pathology and disinhibition circuit. NRHypo produces several other effects. Dragunow and Faull (1990) reported that MK-801 induced the production of c-Fos protein in these same neurons and, not only c-Fos, but other immediate-early genes, including c-Jun, Jun-B, NGFI-A [a.k.a. zif268, krox-24], NGFI-B, NGFI-C and Nurr1 (Farber and Newcomer, in press), are activated by NRHypo. In addition, the heat shock protein HSP70 and its mRNA are induced by NRHypo (Sharp et al., 1991; Olney et al., 1991). Lastly, NRHypo induces the expression of brain derived growth factor mRNA (Hughes et al., 1993; Castren et al., 1993). The ability of some of the same pharmacological treatments, which have been shown to prevent NRHypo neurotoxicity, to prevent these other responses (Farber and Newcomer, 2002) suggests that these other responses may be secondary to activation of the same NRHypo disinhibition mechanism. Consistent with this proposal, PCP's induction of c-Fos and HSP70 has a similar age-dependency profile (Sharp et al., 1992; Sato et al., 1997), as does MK-801 induction of the reversible form of NRHypo neurotoxicity (Farber et al., 1995b).

NRHypo-Induced Psychosis

A variety of NMDA antagonists (e.g., ketamine, PCP, CPP, CPP-ene, CGS19755, CNS 1102) cause a psychotic state in humans (Farber and Newcomer, in press). These findings suggest that a NRHypo state might be involved in the pathophysiology of psychotic disorders. While schizophrenia has received the most attention as the disorder in which an NRHypo state might exist (e.g. Olney and Farber, 1995), the fact that NMDA antagonists can produce maniacal excitation, catatonic signs and euphoria suggests that such a NRHypo state also could be responsible for some of the signs and symptoms of bipolar and schizoaffective disorder (Farber and Newcomer, 2001).

Based upon several intriguing parallels between NRHypo neurotoxicity and NRHypo-induced psychosis, it has been proposed (Olney and Farber, 1995; Farber et al., 1999, Farber and Newcomer, 2002) that the complex polysynaptic disinhibition mechanism that underlies the neurotoxic action of NMDA antagonists also underlies their psychotomimetic effects. This model proposes that mild elevations in the release of acetylcholine and Glu induced by mild NRHypo result in functional over-activation of cerebrocortical neurons and their projection fields, producing cognitive and behavioral disturbances without neurotoxicity. More severe NRHypo causes greater increases in the amount of excessive transmitter release and in the degree of postsynaptic m3 and non-NMDA receptor over stimulation, resulting in neurotoxicity. While the exact role that a NRHypo-disinhibited state plays in idiopathic psychotic disorders like schizophrenia is mostly hypothetical, the data in rodents point to the importance of NMDA receptor-bearing GABAergic interneurons in certain cortical and thalamic regions. Consistent with this conclusion are reports of deficiencies in GABAergic and NMDA/glutamatergic systems in cortical and thalamic regions of subjects with schizophrenia and other idiopathic psychotic disorders (Woo et al., 1998; Benes, 1999; Guidotti et al., 2000; Ibrahim et al., 2000).

NRHypo and Neurodegeneration in Alzheimer’s Disease

One of the first sites of impaired glucose metabolism in Alzheimer’s disease (AD) patients with early memory impairment is in posterior cingulate cortex (Minoshima et al., 1997) and this includes RSC. An important basis for postulating that NRHypo may play a role in AD is that the disseminated pattern of irreversible neuronal degeneration induced in the adult rat brain by NMDA antagonists (Corso et al., 1997; Wozniak et al., 1998) resembles the pattern of neurofibrillary degeneration in AD. In addition, pyramidal neurons are most vulnerable to NRHypo degeneration and they are also the cell types most vulnerable in AD. Thus, the NRHypo disinhibition model of neurotoxicity could offer a partial explanation for the distribution pattern of neurodegeneration in AD.

Hypofunction of the NMDA receptor system, which is the condition that triggers neurodegeneration in the NRHypo model, is a condition present in the normal aging brain and may be present, to a more exaggerated degree, in the brains of AD patients (Olney et al., 1997). Moreover, it is generally agreed that loss of synaptic complexes is the specific neuropathological change that correlates most closely with cognitive deterioration in AD. The neurotoxicity induced by NMDA antagonists involves the selective deletion of dendritic spines and large numbers of synaptic complexes (Corso et al., 1997; Wozniak et al., 1998) and these changes induced by NMDA antagonists are associated with memory loss in rodents (Wozniak et al., 1996; Brosnan-Watters et al., 1996, 1999). In addition, although hyperphosphorylation of tau protein has been proposed as a mechanism to link neurofibrillary tangle (NFT) formation, only limited headway has been made in understanding the mechanisms that initiate and drive the hyperphosphorylation process. The NRHypo mechanism entails excessive activation of transmitter receptors on the surface of the types of neurons that degenerate in AD and these receptors are linked to second messenger systems which, if hyperactivated, might provide the driving force for a hyperphosphorylation process. Based on these considerations it has been proposed that the NRHypo mechanism acts in concert with amyloid deposition in a multiphase process that results in AD (Olney et al., 1997; Farber et al., 2002c).

Comparison of Medial Cortex in Rat and Monkey

One of the reasons for employing a modification of Brodmann’s original scheme for rodent and primate species is to assure that direct comparisons can be made among species and support a rational process for devising models of human disease. This type of analysis does not presume evolutionary or developmental relationships, although homologies may exist. Rather, it states that areas on the medial surface in all mammalian species undergo a series of architectural transitions and that each area evaluated in this context provides for a direct comparison and areas with the same relative position may be similar among species. Demonstration of similarities between areas in different species and use of a common nomenclature does not imply that two areas with the same designation are exactly equivalent; only that they share enough similarity to explore common mechanisms of disease. Here we consider relations between rat and rhesus monkey.

Figure 13 shows the medial surface of both animals with the areas delimited. Areas in monkey cortex that do not appear to have a rodent counterpart are mainly in the cingulate sulcus and include areas 24c, 24c´, 24d as well as the gyral areas 23 and 31. The cingulate sulcus in the monkey was opened so this point could be better appreciated. Although the cingulate motor areas on monkey in areas 24c´ and 24d are not present in rat, there is a part of cingulate cortex in rat that projects to the spinal cord including areas 32 and 24b and it overlaps with AGm (Miller, 1987). Area 24b could be homologous to the rostral cingulate motor area in primates; however, this conclusion suggests that cingulate skeletomotor activity in rat is mediated by pACC, while that in monkey is associated with MCC indicating a very different role of these projections to spinal cord in rat than in monkey.

Success modeling human disease with rodents depends onfinding similarities among the medial surfaces of rat and different primate species. Here cingulate areas in rat and monkey are outlined in photographs at the same magnification. In the monkey the cingulate sulcus was separated (double arrow) to expose the depths of the cingulate sulcus; the splenium of the corpus callosum was warped ventral from the point marked with small dots so the depths of the callosal sulcus can be appreciated. Area 25 in both species is shadowed as are areas 29 and 30 in both species. Although similar cortical regions are smaller in rat, the pericallosal areas in monkey are shown; areas 25, 32, 24a/b, 24a´/b´, and 29a-c, 30. Two regions that do not have counterparts in the rat include monkey areas in the cingulate sulcus (24c, 24c´, 24d) and on the posterior cingulate gyrus (23, 31). The greatest similarity between rat and monkey is in the structure of pericallosal areas.

The massive posterior cingulate gyral surface of primates has no equivalent in rodents, since monkey areas 23a, 23b, and 31 on the gyral surface and area 23c in the caudal cingulate sulcus cannot be identified in rat. RSC in the rodent is comprised of granular area 29 and dysgranular area 30 and this cortex forms the entire PCC in this species. While areas 29 and 30 in the rat are similar to those in primates, these latter areas are actually buried in the callosal sulcus in monkey rather than forming the gyral surface as in rat. The corpus callosum in the monkey in Figure 13 was warped ventrally to expose the depths of the callosal sulcus and demonstrate the retrosplenial areas therein. Areas 23a, 23b and 31, which are on the surface of the posterior cingulate gyrus in monkey and area 23c in the caudal cingulate gyrus together form the PCC in primates and do not appear to have counterparts in the rat. Rose and Woolsey (1948) emphasized this fact by lauding M. Rose’s observations with their following observation: "Area 23 as determined by Brodmann in the rabbit, by Krieg in the rat and by virtually all others except M. Rose, who denied its existence in the rodents, is not likely to exist in any of the loci which have been labeled 23 on rodent cortical maps. M. Rose was obviously right in maintaining that in the rodent’s cortex there is nothing resembling area 23 of carnivores and primates. What appears to be its equivalent area in the rodents has such an outspoken ‘retrosplenial’ appearance that no student of architectonics ever has suggested that it may be equivalent to area 23 in higher forms."

Approximately equivalent areas between the rat and monkey include the following. 1) Area 25 (shaded in both in Figure 13) has a subgenual position. 2) Area 32 is rostral to area 24 in both species. 3) Areas 24a/b and 24a´/b´ have equivalents, although in the rat these areas comprise the entire perigenual and midcingulate regions. 4) Although there is no direct equivalent for the primate sulcal cingulate motor areas 24c´ and 24d in the rat, there are a moderate number of corticospinal projection neurons in rat cingulate cortex as noted above and this supports the notion of a spinal connection, though not from an area that is similar in these species. The different origins of corticospinal projections underscores the less differentiated functions of each rodent cingulate area in contrast to monkey cortex where the corticospinal projections are differentiated into motor areas that are separated from gyral divisions of area 24´. 5) Areas 29a-c appear similar to areas 29l and 29m in monkey and rat area 30 is similar to monkey area 30. Thus, similarities between rat and monkey medial cortices are most prominent in the pericallosal areas.

Even when an area appears to have a similar laminar organization and position in cortical differentiation trends (i.e., periallocortex, proisocortex, isocortex), differences can exist at the connection and cellular levels. At the level of extrinsic connections, it was noted above that corticospinal projections arise from areas in pACC in rat rather than in MCC as in monkey. Also, the primary and secondary visual cortices have major and reciprocal connections with area 29 in rat; however, these do not exist in monkey (Vogt and Pandya, 1987). At the cellular level, even though granular area 29 in rat has a similar counterpart in the monkey, they are not cytologically equivalent. Indeed, the fusiform and extraverted pyramids in rat layers II and III in area 29 have not been observed in monkey (Vogt, 1976; Vogt and Peters, 1981). Finally, at the receptor expression level, presynaptic heteroreceptor organization appears to be different. The presynaptic M2 binding in layers Ia and IV that is so clear in rat has not been observed in monkey (Vogt et al., 1997) where layer I has little dendritic arborization and only weak overall binding for many transmitter receptors due to the presence of a myelin rich fiber tract passing through layer I (taenia tecta).

In spite of the differences between rat and monkey, the essential architecture of pericallosal areas is similar in both species and the rat cortex has significant value as a potential model for certain diseases including neurodegenerative and pharmacological models of psychiatric disease. Given the less differentiated connections, intrinsic organization, and functions of rodent areas, it is unlikely these differences can be overlooked when assessing the mechanisms of cell death and dysfunction. Indeed, rodent models must be considered in the context of these unique morphological and functional properties.

Rodent Models of Disease

Morphology at all levels of analysis provides a basis for assessing the extent to which the rat can be used to model primate diseases. If the pericallosal areas play an important role in the onset and/or progression of a disease, the rat is an appropriate choice for model development. However, if the cingulate sulcal or posterior cingulate gyral areas are the primary target, the rodent is not an appropriate animal. Even when pericallosal areas are the primary region of interest, intrinsic differences among rat and primate species could restrict the value of the rat as a model system. For example, although the rat is often used to study the mechanisms of diseases of the basal ganglia, the human has substantially more calretinin-expressing neurons than does the rat and, to the extent that mechanisms of neurodegeneration in movement disorders depend on the calcium-buffering properties of these neurons in human, rat may not be a useful model of these diseases (Wu and Parent, 2000). Indeed, the cytology, connections, and transmitter receptors expressed by afferent axons to area 29 are not the same in rodent and primate and there does not appear to be, for example, heteroreceptor regulation of thalamic afferents in monkey as in rat. Thus, defining animal models for cortical diseases involves determining which areas are similar and the extent to which similar areas have the same organization.

Although the rat has areas 25 and 24a/b that have a similar relative degree of laminar differentiation as in monkey, the rodent has cingulospinal projections that originate from the pACC rather than the cingulate motor areas, which it does not have. Aspects of neurodegeneration in multiple systems atrophy, therefore, may not be ideal candidates for study in rodent cortex. Furthermore, although RSC receives anterior thalamic afferents in rodents and primates, muscarinic, presynaptic heteroreceptors regulate these terminals in rat but not in primate (Vogt et al., 1997). The import of this difference is currently unclear; however, this difference provides a unique opportunity to determine the importance of these receptors in the rodent and what beneficial or detrimental consequences their absence has for primates.

In this chapter we discussed the neurotoxic effects of NMDA antagonists in rodents and how these effects could shed light on certain diseases like schizophrenia and Alzheimer’s disease. An important step that remains is to determine whether a similar neurotoxicity can be induced in non-human primate brain. Obviously, finding similar damage in similar brain regions would be important for advancing our understanding of human physiology and pathophysiology and would testify to the importance of using the NRHypo rodent model to study primate CNS function and disease. However, not finding similar damage in similar brain regions would also provide beneficial information and potentially could be important over the long run for understanding of the primate brain. Finding NRHypo neurotoxicity in non-RSC areas would provide information about the importance of NRHypo neurotoxicity for human biology and may shift interpretations of the psychogenic properties of dissociative anesthetics. Neurotoxicity in other regions in primates might produce the cognitive and behavioral changes (e.g., psychosis) seen with NMDA antagonists.

Ultimately, specifying animal models of human diseases is a dynamic process of refining the cellular and molecular mechanisms of brain structure and function. For example, identifying the distribution of amyloid-_ peptide in early cases of Alzheimer’s disease led to in vitro and in vivo studies of its neurotoxic properties. This led to analysis of its deposition in murine transgenic models that deleted either or both presenilin genes and mutating the amyloid precursor protein gene. Although no one would suggest that behavioral and structural changes in the mouse are equivalent to those in human, the actions of these genes and previous studies in rat and monkey are now serving as a basis for exploring new therapeutic interventions in human clinical trails. Continued progress in understanding the mechanisms of human disease will depend upon hypotheses and mechanistic findings generated via the dynamic interchange among research activities using many mammalian species and a systematized nomenclature serves as a platform for this process.

Text Abbreviations

ac
ACC
AChE
AD
AGm
A/P
AV
BDA
CYP/IPT
DAMGO
Glu
HRP
KA
LD
MCC
NeuN
NMDA
NRHyper
NRHypo
OXO-M
pACC
Post/Ps
PrS
PZ
RSC
Sub
anterior commissure
anterior cingulate cortex; comprises perigenual & midcingulate regions
acetylcholinesterase
anterodorsal thalamic nucleus and Alzheimer’s disease
medial agranular motor cortex; also related to M2 and area 6/8
anterior/posterior coordinates
anterioventral thalamic nucleus
biotinylated dextran amine
cyanopindolol/isoproterenol
Tyr-D-Ala-Gly-MePhe-Gly-ol
glutamate
horseradish peroxidase
kanic acid
laterodorsal thalamic nucleus
midcingulate cortex
antibody to a neuron-specific neuron nuclear binding protein
N-methyl-D-aspartate
NMDA receptor hyperfunction
NMDA receptor hypofunction
oxotremorine M
perigenual anterior cingulate cortex
postsubiculum
presubiculum
pirenzepine
retrosplenial cortex
subiculum

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