LOSS OF NUCLEUS BASALIS MAGNOCELLULARIS, BUT NOT SEPTAL, CHOLINERGIC NEURONS CORRELATES WITH PASSIVE AVOIDANCE IMPAIRMENT IN RATS TREATED WITH 192-SAPORIN

intraventricular injection of the immunotoxin,192-sap,that selectively de stroys neurons expressing the low affinity neurotrophin receptor,p75NGFr,efficiently and selectively destroys the cholinergic neurons of the hasal forebrain(CBF).In the present study,we sought to determine if there was a correlation between the degree of CBF neuron loss and alteration in passive avoidance behavior.Anesthetized,adult, male Sprague Dawley rats were stereotactically injected with 4μg of either 192-sap or OX7-sap,a control immunotoxin that recognizes the Thy 1 surface antigen and destroys cerebellar Purkinje neu rons. 6￣8 weeks later,immunotoxin and naive control rats were tested on step-through passive avoidance paradigm. After behavior-testing, all rats were sacrificed and brain sections processed for histochemical demonstration of AChE and immunohistochemical demonstration of p75NGFr.The numbers of neurons in specific regions of the CBF were counted from the P75NGFr,staining and the intensity of dorsolateral neocortical staining for AChE were assessed using image analysis. The magnitude of cell loss was similar(67 % ￣70%) for the entire CBF, the Nbm and septum/DBB. The seventy of passive avoidance impairment was significantly correlated to cell loss in the entire CBF (r= 0.748,23 df, P<0.001) and in the Nbm (r = 0.778, 23 df, P< 0.001) but not the septum/DBB (r=0. 419,23 df, P>0. 05).Behavioral impairment also correlated significantly to loss of conical AchE staining intensity ipsilateral to the intraventricular injections (r = 0.796,15df,P< 0.001).These fndings show that loss of Nbm, but not of septum/DBB,cholinergic neurons is proportional to impairment in passive avoidance behavior suggesting a role for Nbm-neocortex cholinergic innervation in this type of learning.(Supported by the Department of Veterans Affairs.)

A mouse model of weight-drop closed head injury:emphasis on cognitive and neurological deficiency

Traumatic brain injury（TBI） is a leading cause of death and disability in individuals worldwide.Producing a clinically relevant TBI model in small-sized animals remains fairly challenging.For good screening of potential therapeutics,which are effective in the treatment of TBI,animal models of TBI should be established and standardized.In this study,we established mouse models of closed head injury using the Shohami weight-drop method with some modifications concerning cognitive deficiency assessment and provided a detailed description of the severe TBI animal model.We found that 250 g falling weight from 2 cm height produced severe closed head injury in C57BL/6 male mice.Cognitive disorders in mice with severe closed head injury could be detected using passive avoidance test on day 7 after injury.Findings from this study indicate that weight-drop injury animal models are suitable for further screening of brain neuroprotectants and potentially are similar to those seen in human TBI.

Basic fibroblast growth factor improves learning and memory functions in chronic stress mice

Four weeks of uncertain stress was used to establish an animal model of chronic stress. Basic fibroblast growth factor was injected daily for 15 days following stress induction. Cell morphology in the hippocampal CA3 region of chronic stress mice revealed cell damage. Nitric oxide content and calcium concentration were significantly increased in the hippocampus, and learning and memory functions were significantly decreased. After basic fibroblast growth factor intervention, Ca2~ overload was decreased and neuronal damage was relieved in hippocampal neurons, which improved learning and memory functions in chronic stress mice. Latency was prolonged and the number of errors was decreased in a passive avoidance test.

Behavioral Evidence for Cognitive Dysfunctions in the(BALB/cByJ-Kv1.1mceph/mceph)Mouse Model for Epilepsy

The epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph (mceph/mceph) is homozygous for a spontaneous mutation truncating the Shaker-like voltage gated potassium channel, Kv1.1 (Kcna1). The mceph/mceph mice are asymptomatic at birth, but develop from 3 weeks of age epileptic seizures, overgrowth and neuronal hyperplasia of the hippocampus. Hippocampal cognitive function of the mice was examined by investigating emotional memory using the aversive Passive Avoidance (PA) task combined with studies of explorative behavior using the non-aversive Novel Cage test (NCT). The behavioural results were examined by multivariate analysis. Compared to wild type and heterozygous mice, the mceph/mceph mice displayed lower exploratory and safety assessment behavior in the NCT and impairment in PA retention 24 hours after training, indicating an impairment in cognitive functions. In conclusion, the epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph, with chronic epilepsy related to potassium-channelopathy, display a behavioural phenotype characterized by impairments in emotional memory and defensive motivational responses probably related to hippocampal dysfunctions.

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.

Involvement of basolateral amygdala GABAA receptors in the effect of dexamethasone on memory in rats

In this study we investigated whether GABAA receptors of the basolateral amygdala(BLA) interact with the effect of dexamethasone on the retrieval stage of memory.Adult male Wistar rats were bilaterally cannulated in the BLA by stereotaxic surgery.The animals were trained in step-through apparatus by induction of electric shock(1.5 mA,3 s) and were tested for memory retrieval after 1 d.The time of latency for entering the dark compartment of the instrument and the time spent by rats in this chamber were recorded for evaluation of the animals' retrieval in passive avoidance memory.Administration of dexamethasone(0.3 and 0.9 mg/kg,subcutaneously(s.c.)),immediately after training,enhanced memory retrieval.This effect was reduced by intra-BLA microinjection of muscimol(0.125,0.250 and 0.500 μg/rat),when administered before 0.9 mg/kg of dexamethasone.Microinjection of bicuculline(0.75 μg/rat,intra-BLA) with an ineffective dose of dexamethasone(0.1 mg/kg,s.c.) increased memory retrieval.However,the same doses of muscimol and bicuculline without dexamethasone did not affect memory processes.Our data support reports that dexamethasone enhances memory retrieval.It seems that GABAA receptors of the BLA mediate the effect of dexamethasone on memory retrieval in rats.