Akinori Ueki

Effects of cholinergic drugs on learning impairment in ventral globus pallidus-lesioned rats

The excitotoxin kainic acid (10 nmol/microliter) was used to produce bilateral lesions in the nucleus basalis magnocellularis (NBM) of rats which provides extensive cholinergic innervation to the cerebral cortex. The behavioral effects of physostigmine, THA (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrate hydrochloride) were investigated by observing locomotor activity, shock sensitivity and passive avoidance response in the NBM-lesioned rats. Evaluation of locomotor activity and shock sensitivity in the experimental animals did not reveal any sensorimotor disturbances caused by the lesions. Oral administration of 1 and 2 mg/kg physostigmine reduced the locomotor activity in the NBM-lesioned rats, while physostigmine (0.5 mg/kg), THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) had no effect on locomotor activity. Compared with the sham-operated controls, the NBM-lesioned rats exhibited a significantly lesser deficit in the retention of the passive avoidance response. THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) elicited good retention of the passive avoidance response. Rats with NBM lesions showed impaired acquisition of a passive avoidance response when trained repeatedly at 24-h intervals. Also, when post-training NBM lesions were induced, there was rapid extinction of the acquired passive avoidance response. THA or NIK-247 administered at doses of 3 mg/kg significantly increased response latencies of post-trained NBM-lesioned rats. THA or NIK-247 administered once a day in doses of 1 or 3 mg/kg p.o. produced a very significant increase of acetylcholine in the cerebral cortex of NBM-lesioned rats after the 21st administration. These finding suggest that THA and NIK-247 exert an ameliorating effect on memory disturbance induced by NBM lesions in rats.

Prepulse inhibition of acoustic startle response in mild cognitive impairment and mild dementia of Alzheimer type

Abstract  Amnestic mild cognitive impairment (MCI) describes the condition of memory‐impaired individuals who otherwise function well and do not meet the clinical criteria for dementia. Such individuals are considered to represent a transitional stage between normal aging and dementia of Alzheimer type (DAT). Neurobiologic changes in amnestic MCI, and their significance for psychophysiologic function, are poorly understood. In this study, the authors compared acoustic prepulse inhibition (PPI) between subjects with amnestic MCI and mild DAT to characterize sensorimotor gating. The acoustic startle reflex, which the authors measured using an accelerometer and electromyogram, involves whole‐body movement and eye blink in response to a sudden loud noise (115 dB). PPI is inhibition of this reflex by a softer noise (prepulse; 85 dB) preceding the startle stimulus by 30 ms. PPI was examined in 30 controls, 20 subjects with amnestic MCI, and 20 subjects with mild DAT. Neither amnestic MCI nor mild DAT affected startle movement amplitude. Subjects with amnestic MCI showed significantly enhanced PPI (gating facilitation), while subjects with mild DAT exhibited significantly less PPI than controls (gating deficit). This pattern of PPI changes suggests that neuropathologic changes in the limbic cortex, mainly the entorhinal cortex, at the earliest stage of DAT might be responsible for PPI abnormalities via disturbed regulation of the limbic cortico‐striato‐pallido‐pontine circuitry. Startle PPI changes could be used as a biologic marker for amnestic MCI and mild DAT.

Impairment in the acquisition of passive and active avoidance learning tasks due to bilateral entorhinal cortex lesions

The relationship between the entorhinal cortex and learning behavior was examined. The initial stage of Alzheimers disease has been shown to be characterized by neuropathological alteration in the entorhinal cortex, with the appearance of the greatest number of neuronal tangles and severe neuronal loss in comparison with other brain regions involved. This entorhinal cortex, because of its anatomical relationship to the hippocampus, may play a crucial role in memory formation. In this study, rats with bilateral ibotenic acid-induced lesions of the entorhinal cortices were tested for acquisition of passive and active avoidance learning tasks. These animals displayed no sensorimotor disturbances as shown by evaluation of locomotor activity and shock sensitivity. However, they did show impair acquisition of passive and active avoidance responses. On the other hand, when the lesions were induced after training, there was no extinction of the acquired passive and active avoidance responses. The results demonstrate the importance of the entorhinal cortex in learning acquisition and indicate that rats with partial neuronal loss in the entorhinal cortex may be a useful model for studying the memory disturbance of Alzheimers disease.

Serotonin Transporter Gene Polymorphism and BPSD in Mild Alzheimer's Disease

The purpose of the present study was to confirm an association of functional polymorphism within the serotonin transporter (5-HTT) gene with Alzheimers disease (AD) and behavioral and psychological symptoms of dementia (BPSD) in mild AD. Apolipoprotein E (ApoE) gene polymorphism and 2 types of functional polymorphism in the 5-HTT gene, 5-HTT-linked polymorphic region (5-HTTLPR) and a 5-HTT variable number of tandem repeats sequence (5-HTTVNTR) were analyzed longitudinally in outpatients with mild AD to find out whether there was a relation between any such polymorphisms and the occurrence of BPSD. No significant differences in genotype distribution or allele frequencies were identified for 5-HTTLPR or 5-HTTVNTR between AD patients and age- and sex-matched non-demented controls regardless of ApoE epsilon4 allele. No significant differences were noted in 5-HTTLPR genotype or allele distributions between AD patients with or without BPSD. However, significant associations were observed between presence of 5-HTTVNTR allele 10 and BPSD or aggressiveness. This difference was independent of the presence of the ApoE epsilon4 allele. As a result, 5-HTT polymorphisms are unlikely to play any substantial role in susceptibility to AD. Conversely, 5-HTTVNTR influences the risk of developing BPSD or aggressiveness and genetic variations in the 5-HTT gene may be involved in the development of symptomatology for mild AD.

Reduced prepulse inhibition in rats with entorhinal cortex lesions.

The relationship between the entorhinal cortex and prepulse inhibition (PPI) as well as dopaminergic participation in this relationship were examined. PPI is an operational measure of sensorimotor gating in which a robust response to a startling auditory pulse stimulus is inhibited when the stimulus is preceded by a weak prepulse. PPI can be measured in various species and is reduced in several neuropsychiatric disorders and in dopamine-activated rats. The entorhinal cortex was damaged bilaterally using ibotenic acid, and acoustic startle experiments were performed during treatment with haloperidol or saline on day 21 after the ibotenic acid injection. Neither this injection nor haloperidol affected the amplitude of the startle movement. Bilateral entorhinal cortex lesions reduced PPI, while haloperidol partially restored it. The entorhinal cortex and the sensorimotor gating system therefore may be related via dopaminergic circuits, possibly including the nucleus accumbens. Further, as the entorhinal cortex provides the major extrinsic synaptic input to the rat hippocampus, disease involvement of this region may severely affect cognition in various disorders including schizophrenia.

Synapse alteration in hippocampal CA3 field following entorhinal cortex lesion

To model one aspect of the neurodegeneration observed in Alzheimers disease and to investigate the synaptic alteration of the hippocampus associated with entorhinal cortex lesion, ibotenic acid was used to produce selective unilateral neuronal loss in rat entorhinal cortex. Immunohistological and microdensitometrical analyses confirmed ibotenic acid lesion of the entorhinal cortex after 3 months and showed a decrease of synaptophysin-immunoreactive substances in the stratum lucidum of the CA3 field. This study demonstrates that entorhinal cortex lesion can lead to synaptic alterations and cause damage to presynaptic terminals with projecting area in the disruption of the entorhinal cortex hippocampus relay passage.

Depression in multiple system atrophy: A case report

Abstract A 53‐year‐old woman who developed depression as the first symptom of multiple system atrophy was treated. Depression was followed successively by autonomic failure, parkinsonism and cerebellar ataxia. Treatment with L‐DOPA, L‐threo‐DOPS, and thyroid releasing hormone was associated with improvement of autonomic failure and parkinsonism. As for depression, scores on the Zung scale and the Hamilton scale improved from 58 to 49 and from 30 to 22, respectively. This case is remarkable in that depression preceded neurologic dysfunction and was managed successfully by antiparkinsonian medication. A common underlying disturbance may be responsible for the depression and neurologic dysfunction in multiple system atrophy.

Effects of entorhinal cortex lesion on learning behavior and on hippocampus in the rat

The initial stage of Alzheimers disease is characterized by a neuropathological change in the entorhinal cortex. In a previous study it was shown that rats with excitotoxic lesion of entorhinal cortex showed an impaired acquisition of passive and active avoidance responses. In this study a rat with excitotoxic lesion of the entorhinal cortex was tested for ‘more operant’ behavioral learning (i.e., positive reinforcement operant learning). The hippocampus was also examined histologically as acetylcholinesterase‐stained sections, and as synaptophysin immunostained sections and examined biochemically by liquid chromatography. Eight weeks after operation, the bilateral entorhinal cortex lesioned rats showed an impaired acquisition of positive reinforcement operant learning. The lesioned side of unilateral entorhinal cortex lesioned rats showed a decrease of acecylcholinesterase‐positive fibers in the CA3, the dentate gyrus, and of synaptophysin‐positive substances in the CA3. Biochemical study showed a decreased level of acetylcholine in the CA3, and in the dentate gyrus. The histological and biochemical findings are interpreted as indicating that the entorhinal cortex of the rat provides the major extrinsic synaptic input to the hippocampal formation via the circuit which serves as a relay passage through the dentate gyrus and via direct projections into the hippocampus. Behavioral findings confirmed the importance of the entorhinal cortex in memory acquisition and indicated that rats with a partial neuronal loss in the entorhinal cortex may be a useful model for the memory disturbance of Alzheimers disease.

Histological evidence for cholinergic alteration in the hippocampus following entorhinal cortex lesion

The initial stage of Alzheimers disease is characterized by neuropathological alteration in the entorhinal cortex. To model one aspect of the neurodegeneration observed and to investigate anatomical changes of the hippocampus associated with unilateral entorhinal cortex lesion, excitotoxin ibotenic acid was used to produce selective unilateral neuronal loss in rat entorhinal cortex. Histological and morphometrical analyses confirmed excitotoxic lesion of the entorhinal cortex after 3 months and showed a decrease of acetylcholineste-rase-stained fibers in the stratum moleculare of the dentate gyrus and the stratum radiatum of the CA3 field. This study demonstrates the importance of the entorhinal cortex in the hippocampal cholinergic function which appears to be important to memory and learning, and raises the possibility that memory deficit in Alzheimers disease may be associated with partial neuronal loss in the entorhinal cortex.

Dopamine D3 Receptor Gene Polymorphism Influences on Behavioral and Psychological Symptoms of Dementia (BPSD) in Mild Dementia of Alzheimer's Type

Dopamine D3 receptor (DRD3) is present in the limbic system, which is thought to regulate affect, cognition, and activity. Thus a functional change in the DRD3 gene could in turn affect the cognitive and psychiatric symptoms of dementia of Alzheimers type (DAT). We investigated a possible association of DRD3 genotype with DAT and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for DRD3 and apolipoprotein E (ApoE) was determined using restriction fragment length polymorphism in 210 patients with mild DAT and 224 age- and sex-matched non-demented controls. The occurrence of BPSD during the course of mild dementia was demonstrated using the Behavioral Pathology in Alzheimers Disease rating scale (BEHAVE-AD). No significant differences in DRD3 genotype were identified between DAT and controls, regardless of ApoE epsilon4. Among the DAT with BPSD, however, a significant association was observed between the presence of the DRD3 glycine allele and paranoid and delusional ideation, regardless of ApoE epsilon4. In conclusion, DRD3 gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of paranoid and delusional ideation during the course of mild DAT.