Chronic cognitive deficits and amyloid precursor protein elevation after selective immunotoxin lesions of the basal forebrain cholinergic system

The biological response of bone marrow to incorporated radionuclides depends on several factors such as absorbed dose, dose rate, proliferation and marrow reserve. The determination of the dose rate and absorbed dose to bone marrow from incorporated radionuclides is complex. This research used survival of granulocyte-macrophage colony-forming cells (GM-CFCs) as a biological dosimeter to determine experimentally the dose rate and dose to bone marrow after administration of 90Y-citrate. METHODS: The radiochemical 90Y-citrate was administered intravenously to Swiss Webster mice. Biokinetics studies indicated that the injected 90Y quickly localized in the femurs (0.8% ID/femur) and cleared with an effective half-time of 62 hr. Subsequently, GM-CFC survival was determined as a function of femur uptake and injected activity. Finally, to calibrate GM-CFC survival as a biological dosimeter, mice were irradiated with external 137Cs gamma rays at dose rates that decreased exponentially with a half-time of 62 hr. RESULTS: Femur uptake was linearly proportional to injected activity. The survival of GM-CFCs was exponentially dependent on both the initial 90Y femur activity and the initial dose rate from external 137Cs gamma rays with 5.1 kBq/femur and 1.9 cGy/hr, respectively, required to achieve 37% survival. Thus, 90Y-citrate delivers a dose rate of 0.37 cGy/hr to the femoral marrow per kBq of femur activity and the dose rate decreased with an effective half-time of 62 hr. CONCLUSION: Survival of GM-CFCs can serve as a biological dosimeter to experimentally determine the dose rate kinetics in bone marrow.     

Morphological and membrane properties of rat magnocellular basal forebrain neurons maintained in culture

Morphological and electrophysiological characteristics of magnocellular neurons from basal forebrain nuclei of postnatal rats (11-14 days old) were examined in dissociated cell culture. Neurons were maintained in culture for periods of 5-27 days, and 95% of magnocellular (>23 micron diam) neurons stained positive with acetylcholinesterase histochemistry. With the use of phase contrast microscopy, four morphological subtypes of magnocellular neurons could be distinguished according to the shape of their soma and pattern of dendritic branching. Corresponding passive and active membrane properties were investigated with the use of whole cell configuration of the patch-clamp technique. Neurons of all cell types displayed a prominent (6-39 mV; 6.7-50 ms duration) spike afterdepolarization (ADP), which in some cells reached firing threshold. The ADP was voltage dependent, increasing in amplitude and decreasing in duration with membrane hyperpolarization with an apparent reversal potential of -59 +/- 2.3 (SE) mV. Elevating [Ca2+]o (2.5-5.0 mM) or prolonging spike repolarization with 10 mM tetraethylammonium (TEA) or 1 mM 4-aminopyridine (4-AP), potentiated the ADP while it was inhibited by reducing [Ca2+]o (2.5-1 mM) or superfusion with Cd2+ (100 microM). The ADP was selectively inhibited by amiloride (0.1-0.3 mM or Ni2+ 10 microM) but unaffected by nifedipine (3 microM), omega-conotoxin GVIA (100 nM) or omega-agatoxin IVA (200 nM), indicating that Ca2+ entry was through T-type Ca2+ channels. After inhibition of the ADP with amiloride (300 microM), depolarization to less than -65 mV revealed a spike afterhyperpolarization (AHP) with both fast and slow components that could be inhibited by 4-AP (1 mM) and Cd2+ (100 microM), respectively. In all cell types, current-voltage relationships exhibited inward rectification at hyperpolarized potentials >/=EK (approximately -90 mV). Application of Cs+ (0.1-1 mM) or Ba2+ (1-10 microM) selectively inhibited inward rectification but had no effect on resting potential or cell excitability. At higher concentrations, Ba2+ (>10 microM) also inhibited an outward current tonically active at resting potential (VH -70 mV), which under current-clamp conditions resulted in small membrane depolarization (3-10 mV) and an increase in cell excitability. Depolarizing voltage commands from prepulse potential of -90 mV (VH -70 mV) in the presence of tetrodotoxin (0.5 microM) and Cd2+ (100 microM) to potentials between -40 and +40 mV cause voltage activation of both transient A-type and sustained delayed rectifier-type outward currents, which could be selectively inhibited by 4-AP (0.3-3 mM) and TEA (1-3 mM), respectively. These results show that, although acetylcholinesterase-positive magnocellular basal forebrain neurons exhibit considerable morphological heterogeneity, they have very similar and characteristic electrophysiological properties.     

The behavioral effects of the destruction of the magnocellular basal nucleus of the forebrain of cats

Behavioral experiments were carried out in cats following methodology which simulates complexly organized, nonautomatized behavior with elements of generalization and abstraction. A conclusion was reached regarding the participation of this formation in the structural-functional support of complex integrative forms of activity, cognitive and gnostic processes, was reached on the basis of the results of the performance of test tasks by the animals with partial destruction of the magnocellular basal nucleus. The proposed mechanism of the involvement of the basal nucleus in gnostic and cognitive processes is the nonspecific support of the system of structures which participate directly in thinking and learning.     

Sexually dimorphic responses to neonatal basal forebrain lesions in mice: II. Cortical morphology

Previous studies in the mouse have shown that neonatal lesions to the cholinergic basal forebrain (nBM) areas result in transient cholinergic depletion of neocortex and precipitate altered cortical morphogenesis. Lesion-induced morphological alterations in cortex persist into adulthood and are accompanied by behavioral changes, including spatial memory deficits. The current study investigated whether neonatal nBM lesions affect male and female mice differently in adulthood. Quantitative morphometry of cortical layer width was employed to assess alterations in cytoarchitecture in neonatally nBM-lesioned and littermate control mice of both sexes following behavioral testing. Our results showed significant decreases in cortical layer IV and V widths across somato/motor cortex in neonatally nBM lesioned mice of both sexes. Sexually dimorphic responses were observed in cortical layer II/III and total cortical width, limited to the area containing the "barrel cortex" representation of the whisker hairs. In lesioned females, layer II/III and total cortical width were decreased relative to female controls, and in lesioned males, layer II/III was increased relative to controls, whereas total cortical width was unchanged. In male but not female mice we observed significant correlations between decreased widths in layer IV and V and impaired performance on a spatial memory task. The current data further support a role of developing cholinergic cortical afferents in the modulation of cortical morphogenesis and cortical circuits involved in cognitive behaviors. In addition, our observations provide further evidence for sexually dimorphic development and function in cognitive centers of the rodent brain.     

NGF mRNA is expressed by GABAergic but not cholinergic neurons in rat basal forebrain

Nerve growth factor (NGF) supports the survival and biosynthetic activities of basal forebrain cholinergic neurons and is expressed by neurons within lateral aspects of this system including the horizontal limb of the diagonal bands and magnocellular preoptic areas. In the present study, colormetric and isotopic in situ hybridization techniques were combined to identify the neurotransmitter phenotype of the NGF-producing cells in these two areas. Adult rat forebrain tissue was processed for the colocalization of mRNA for NGF with mRNA for either choline acetyltransferase, a cholinergic cell marker, or glutamic acid decarboxylase, a GABAergic cell marker. In both regions, many neurons were single-labeled for choline acetyltransferase mRNA, but cells containing both choline acetyltransferase and NGF mRNA were not detected. In these fields, virtually all NGF mRNA-positive neurons contained glutamic acid decarboxylase mRNA. The double-labeled cells comprised a subpopulation of GABAergic neurons; numerous cells labeled with glutamic acid decarboxylase cRNA alone were codistributed with the double-labeled neurons. These data demonstrate that in basal forebrain GABAergic neurons are the principal source of locally produced NGF.     

Selective immunotoxic lesions of basal forebrain cholinergic cells: Effects on learning and memory in rats.

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cellular localizations of AMPA glutamate receptors within the basal forebrain magnocellular complex of rat and monkey

The cellular distributions of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors within the rodent and nonhuman primate basal forebrain magnocellular complex (BFMC) were demonstrated immunocytochemically using anti-peptide antibodies that recognize glutamate receptor (GluR) subunit proteins (i.e., GluR1, GluR4, and a conserved region of GluR2, GluR3, and GluR4c). In both species, many large GluR1-positive neuronal perikarya and aspiny dendrites are present within the medial septal nucleus, the nucleus of the diagonal band of Broca, and the nucleus basalis of Meynert. In this population of neurons in rat and monkey, GluR2/3/4c and GluR4 immunoreactivities are less abundant than GluR1 immunoreactivity. In rat, GluR1 does not colocalize with ChAT, but, within many neurons, GluR1 does colocalize with GABA, glutamic acid decarboxylase (GAD), and parvalbumin immunoreactivities. GluR1- and GABA/GAD-positive neurons intermingle extensively with ChAT-positive neurons. In monkey, however, most GluR1-immunoreactive neurons express ChAT and calbindin-D28 immunoreactivities. The results reveal that noncholinergic GABAergic neurons, within the BFMC of rat, express AMPA receptors, whereas cholinergic neurons in the BFMC of monkey express AMPA receptors. Thus, the cellular localizations of the AMPA subtype of GluR are different within the BFMC of rat and monkey, suggesting that excitatory synaptic regulation of distinct subsets of BFMC neurons may differ among species. We conclude that, in the rodent, BFMC GABAergic neurons receive glutamatergic inputs, whereas cholinergic neurons either do not receive glutamatergic synapses or utilize GluR subtypes other than AMPA receptors. In contrast, in primate, basal forebrain cholinergic neurons are innervated directly by glutamatergic afferents and utilize AMPA receptors.     

Extensive reinnervation of the hippocampus by embryonic basal forebrain cholinergic neurons grafted into the septum of neonatal rats with selective cholinergic lesions

The immunodominant surface antigen of Toxoplasma gondii, surface antigen 1 (SAG1), was expressed in Escherichia coli as a fusion protein containing a majority of the SAG1 protein supplied with six histidyl residues in the N-terminal end. The recombinant protein was purified on a Ni-chelate column and then on a fast-performance liquid chromatography column and was in a nonreduced condition. It was recognized by T. gondii-specific human immunoglobulin G (IgG) and IgM antibodies as well as by a mouse monoclonal antibody (S13) recognizing only nonreduced native SAG1. Antibodies induced in mice by the recombinant SAG1 recognized native SAG1 from the T. gondii RH isolate in culture. Recombinant SAG1 is suitable for use in diagnostic systems for detecting anti-SAG1-specific IgG and IgM antibodies.     

Some observations on the preference deficits produced by lateral preoptic lesions in the rat.

Conducted 4 experiments with a total of 20 female albino Sherman rats which show that, following water deprivation, Ss with lateral preoptic (LPO) damage lost the normal preference for glucose solutions. Food deprivation reinstated the preference. This dependency was specific to sweet-tasting fluids, and the deficit persisted even when thirst was alleviated prior to the preference test. Such Ss would drink sweet solutions in response to intravascular fluid depletion, but they were deficient in response to sweet solutions under nondeprived conditions. This last finding in particular suggests that hunger and palatibility, as determinants of the response to sweet solutions, may be dissociated by LPO damage. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neonatal 192 IgG-saporin lesions of basal forebrain cholinergic neurons selectively impair response to spatial novelty in adult rats.

The role of the developing cholinergic basal forebrain system on cognitive behaviors was examined in 7 day-old rats by giving lesions with intraventricular injections of 192 IgG-saporin or saline. Rats were subjected to passive avoidance on postnatal days (PND) 22–23, water maze testing on PND 50–60, and a open-field test (in which reactions to spatial and object novelty were measured) on PND 54. Behavioral effects of the lesions were evident only in the open-field test with 5 objects. Unlike controls, the lesioned rats did not detect a spatial change after a displacement of 2 of the 5 objects. Control and lesioned rats, however, showed comparable novelty responses to an unfamiliar object. Lesion effectiveness was confirmed by 75% and 84% decreases in choline acetyltransferase activity in cortex and hippocampus. These results suggest that the developing cholinergic system may be involved in spatial information processing or attention to spatial modifications. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Specificity of avoidance deficits produced by 6-hydroxydopamine lesions of the nigrostriatal system of the rat.

Three experiments with a total of 65 male Wistar rats showed that microinjections of 6-hydroxydopamine (6-OHDA) into the dopaminergic nigrostriatal system (NS) impaired acquisition of a 2-way avoidance response. This effect was independent of nutritional deficiencies since it was observed even when a special postoperative treatment ensured a comparable state of nutrition in control and experimental Ss. It was likewise independent of locomotor disturbances. Because doses of 6-OHDA that impaired acquisition of an active avoidance response produced lesions that were, to a great extent, nonspecific, behavioral effects of these doses cannot be entirely ascribed to selective destruction of the NS. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective induction of c-Jun and NGF in reactive astrocytes after cholinergic degenerations in rat basal forebrain

Cholinergic basal forebrain neurons are the major source of cortical cholinergic innervation. The number of these neurons is regulated by the availability of nerve growth factor (NGF) during development while in adulthood their cholinergic activity is modulated by NGF. In previous studies we have shown that cholinergic immunolesions of basal forebrain neurons increase local immediate early gene expression and NGF synthesis in the regions of degeneration. In this study we identify the cellular source of c-Jun and NGF expression using dual immunolabeling of c-Jun and NGF in combination with neuronal and glial markers. We demonstrate that both c-Jun and NGF are exclusively expressed in reactive astrocytes but not in microglia or in GABAergic basal forebrain neurons. These observations support the hypothesis that reactive astrocytes synthesize neurotrophic substances in vivo in response to neuronal degeneration in the basal forebrain.     

Acidic fibroblast growth factor mRNA is expressed by basal forebrain and striatal cholinergic neurons

Evidence for the importance of the basal forebrain cholinergic system in the maintenance of cognitive function has stimulated efforts to identify trophic mechanisms that protect this cell population from atrophy and dysfunction associated with aging and disease. Acidic fibroblast growth factor (aFGF) has been reported to support cholinergic neuronal survival and has been localized in basal forebrain with the use of immunohistochemical techniques. Although these data indicate that aFGF is present in regions containing cholinergic cell bodies, the actual site of synthesis of this factor has yet to be determined. In the present study, in situ hybridization techniques were used to evaluate the distribution and possible colocalization of mRNAs for aFGF and the cholinergic neuron marker choline acetyltransferase (ChAT) in basal forebrain and striatum. In single-labeling preparations, aFGF mRNA-containing neurons were found to be codistributed with ChAT mRNA+ cells throughout all fields of basal forebrain, including the medial septum/diagonal band complex and striatum. By using a double-labeling (colormetric and isotopic) technique, high levels of colocalization (over 85%) of aFGF and ChAT mRNAs were observed in the medial septum, the diagonal bands of Broca, the magnocellular preoptic area, and the nucleus basalis of Meynert. The degree of colocalization was lower in the striatum, with 64% of the cholinergic cells in the caudate and 33% in the ventral striatum and olfactory tubercle labeled by the aFGF cRNA. These data demonstrate substantial regionally specific patterns of colocalization and support the hypothesis that, via an autocrine mechanism, aFGF provides local trophic support for cholinergic neurons in the basal forebrain and the striatum.     

Role of prefrontal cortex and striatal output systems in short-term memory deficits associated with ageing, basal forebrain lesions, and cholinergic-rich grafts.

Reviews studies demonstrating that cholinergic grafts can ameliorate some deficits in aged animals and in animals with basal forebrain or fimbria-fornix lesions. Additional experiments were conducted with 35 male rats in Exp 1 and 26 female rats in Exp 2. Lesions of the motor and parietal zones of dorsolateral neocortex did not affect Ss' performance on a delayed-matching-to-performance task. Transection of the fimbria-fornix disrupted task performance in a delay-dependent manner, suggesting a specific disruption of short-term retention. Data confirm involvement of the medial prefrontal cortex and its ventral striatal outputs in performance of the task and in age-related deficits in short-term memory. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Recovery of spatial alternation deficits following selective hippocampal destruction with kainic acid.

[Correction Notice: An erratum for this article was reported in Vol 101(5) of Behavioral Neuroscience (see record 2008-10704-001). In the aforementioned article, the degrees of freedom reported in the Results section are incorrect. In the sixth paragraph on page 281, the second sentence should read as follows: Results of the ANOVA indicated a significant effect for surgical treatments. F(2, 25)=25.44, p     

MK-801 prevents brain lesions and delayed-nonmatching-to-sample deficits produced by pyrithiamine-induced encephalopathy in rats.

Rats were trained on a spatial delayed-nonmatching-to-sample (DNMTS) task and assigned by block randomization to 1 of 4 treatments: pyrithiamine-induced thiamine deficiency (PTD), PTD with administration of MK-801 after 12 days, control with MK-801 treatment, and control without MK-801. After 15 days of treatment followed by 21 days of recovery, the PTD rats showed significant deficits for DNMTS accuracy at retention intervals (RIs) that ranged from 3.0 sec to 15.0 sec, the RIs that produced 75% accuracy on DNMTS in staircase training, and the rate at which a novel radial arm maze task was learned. The PTD-treated rats had consistent lesions in the thalamus and the mammillary bodies. MK-801 protected rats from both behavioral deficits and brain lesions (assessed quantitatively and qualitatively) that were produced by the PTD treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Projections of GABAergic and cholinergic basal forebrain and GABAergic preoptic-anterior hypothalamic neurons to the posterior lateral hypothalamus of the rat

Within the basal forebrain, gamma-aminobutyric acid (GABA)-synthesizing neurons are codistributed with acetylcholine-synthesizing neurons (Gritti et al. [1993] J. Comp. Neurol. 329:438-457), which constitute one of the major forebrain sources of subcortical afferents to the cerebral cortex. In the present study, descending projections of the GABAergic and cholinergic neurons were investigated to the lateral posterior hypothalamus (LHp) through which the medial forebrain bundle passes and where another major forebrain source of subcortical afferents is situated. Retrograde transport of cholera toxin b subunit (CT) from the LHp was combined with immunohistochemical staining for glutamic acid decarboxylase (GAD) and choline acetyl transferase (ChAT) using a sequential peroxidase-antiperoxidase (PAP) technique. A relatively large number of GAD+ neurons (estimated at approximately 6,200), which represented > 15% of the total population of GAD+ cells in the basal forebrain (estimated at approximately 39,000), were retrogradely labeled from the LHp. These cells were distributed through the basal forebrain cell groups, where ChAT+ cells are also located, including the medial septum and diagonal band nuclei, the magnocellular preoptic nucleus, and the substantia innominata, with few cells in the globus pallidus. In these same nuclei, a small number of ChAT+ cells were retrogradely labeled (estimated at approximately 800), which represented only a small percentage (< 5%) of the ChAT+ cell population in the basal forebrain (estimated at approximately 18,000). Both the GAD+ and ChAT+ LHp-projecting neurons represented a small subset of their respective populations in the basal forebrain, distinct from the magnocellular, presumed cortically projecting, basal neurons. In addition to the GAD+ cells in the basal forebrain, GAD+ cells in the adjacent preoptic and anterior hypothalamic regions were also retrogradely labeled in significant numbers (estimated at approximately 5,500) and proportion (> 20%) of the total population (estimated at approximately 30,000) from the LHp. The retrogradely labeled GAD+ neurons were distributed in continuity with those in the basal forebrain through the lateral preoptic area, medial preoptic area, bed nucleus of the stria terminals, and anterior and dorsal hypothalamic areas. Of the large number of cells that project to the LHp in the basal forebrain and preoptic-anterior hypothalamic regions (estimated at approximately 66,000), the GAD+ neurons represented a significant proportion (> 15%) and the ChAT+ neurons a very small proportion (approximately 2%). The relative magnitude of the GABAergic projection suggests that it may represent an important inhibitory influence of the descending efferent output from the basal forebrain and preoptic-anterior hypothalamic regions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: Selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density.

Rats were trained in a previously validated behavioral vigilance task that required them to detect visual signals of variable length and to discriminate signal from nonsignal events. Baseline performance was characterized by a signal length-dependent ability to score hits. a decline in hits over time, and a correct rejection rate of approximately 70% After the rats reached criterion performance in this task, the immunotoxin 192 IgG-saporin or its vehicle was infused into the area of the nucleus basalis/substantia innominata of the basal forebrain. Postoperative performance in lesioned rats was characterized by a decrease in their ability to detect signals while their ability to correctly reject nonsignals remained unaffected. The effect of the lesion did not recover in the course of over 180 sessions of postlesion testing. The overall performance of the rats correlated with acetylcholinesterase (AChE)-positive fiber density in all cortical areas measured except the cingulate and pyriform cortex. These findings help to elucidate the nature of the attentional impairments resulting from the loss of cortical cholinergic inputs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A possible role for cholinergic neurons of the basal forebrain and pontomesencephalon in consciousness

Excitation at widely dispersed loci in the cerebral cortex may represent a neural correlate of consciousness. Accordingly, each unique combination of excited neurons would determine the content of a conscious moment. This conceptualization would be strengthened if we could identify what orchestrates the various combinations of excited neurons. In the present paper, cholinergic afferents to the cerebral cortex are hypothesized to enhance activity at specific cortical circuits and determine the content of a conscious moment by activating certain combinations of postsynaptic sites in select cortical modules. It is proposed that these selections are enabled by learning-related restructuring that simultaneously adjusts the cytoskeletal matrix at specific constellations of postsynaptic sites giving all a similar geometry. The underlying mechanism of conscious awareness hypothetically involves cholinergic mediation of linkages between microtubules and microtubule-associated protein-2 (MAP-2). The first reason for proposing this mechanism is that previous studies indicate cognitive-related changes in MAP-2 occur in cholinoceptive cells within discrete cortical modules. These cortical modules are found throughout the cerebral cortex, measure 1-2 mm2, and contain approximately 10(3)-10(4) cholinoceptive cells that are enriched with MAP-2. The subsectors of the hippocampus may function similarly to cortical modules. The second reason for proposing the current mechanism is that the MAP-2 rich cells throughout the cerebral cortex correspond almost exactly with the cortical cells containing muscarinic receptors. Many of these cholinoceptive, MAP-2 rich cells are large pyramidal cell types, but some are also small pyramidal cells and nonpyramidal types. The third reason for proposing the current mechanism is that cholinergic afferents are module-specific; cholinergic axons terminate wholly within individual cortical modules. The cholinergic afferents may be unique in this regard. Finally, the tapering apical dendrites of pyramidal cells are proposed as primary sites for cholinergic mediation of linkages between MAP-2 and microtubules because especially high amounts of MAP-2 are found here. Also, the possibility is raised that muscarinic actions on MAP-2 could modulate microtubular coherence and self-collapse, phenomena that have been suggested to underlie consciousness.     

Comparison of behavioral deficits caused by lesions in septal and ventromedial hypothalamic areas of female rats.

41 female Holtzman rats with lesions in ventromedial hypothalamic (VMH) area and 37 Ss with lesions in septal area were compared with 30 normal Ss for passive-avoidance performance (Exp I), reversal learning (Exp II), and spontaneous alternation (Exp III). Lesions in both septal and VMH areas produced a deficit in passive-avoidance performance, a greater number of errors in reversal learning, and reduced spontaneous alternation in a -maze. The qualitatively similar behavioral deficits produced by septal and VMH lesions suggests that at least part of the functions of both of these areas may overlap in a single system. An attempt was made to identify such a functional system, and an explanation for the behavioral deficits produced by VMH damage was offered. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)