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Loss of noradrenaline (NA)-rich afferents from the Locus Coeruleus (LC) ascending to the hippocampal formation has been reported to dramatically affect distinct aspects of cognitive function, in addition to reducing the proliferation of neural progenitors in the dentate gyrus. Here, the hypothesis that reinstating hippocampal noradrenergic neurotransmission with transplanted LC-derived neuroblasts would concurrently normalize both cognitive performance and adult hippocampal neurogenesis was investigated. Post-natal day (PD) 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents followed, 4 days later, by the bilateral intrahippocampal implantation of LC noradrenergic-rich or control cerebellar (CBL) neuroblasts. Starting from 4 weeks and up to about 9 months post-surgery, sensory-motor and spatial navigation abilities were evaluated, followed by post-mortem semiquantitative tissue analyses. All animals in the Control, Lesion, Noradrenergic Transplant and Control CBL Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task. By contrast, working memory abilities were seen to be consistently impaired in the Lesion-only and Control CBL-Transplanted rats, which also exhibited a virtually complete noradrenergic fiber depletion and a significant 62–65% reduction in proliferating 5-bromo-2′deoxyuridine (BrdU)-positive progenitors in the dentate gyrus. Notably, the noradrenergic reinnervation promoted by the grafted LC, but not cerebellar neuroblasts, significantly ameliorated working memory performance and reinstated a fairly normal density of proliferating progenitors. Thus, LC-derived noradrenergic inputs may act as positive regulators of hippocampus-dependent spatial working memory possibly via the concurrent maintenance of normal progenitor proliferation in the dentate gyrus. [ABSTRACT FROM AUTHOR]

Abstract: Extensive loss of noradrenaline‐containing neurons and fibers is a nearly invariant feature of Alzheimer's Disease (AD). However, the exact noradrenergic contribution to cognitive and histopathological changes in AD is still unclear. Here, this issue was addressed following selective lesioning and intrahippocampal implantation of embryonic noradrenergic progenitors in developing rats. Starting from about 3 months and up to 12 months post‐surgery, animals underwent behavioral tests to evaluate sensory‐motor, as well as spatial learning and memory, followed by post‐mortem morphometric analyses. At 9 months, Control, Lesioned and Lesion + Transplant animals exhibited equally efficient sensory‐motor and reference memory performance. Interestingly, working memory abilities were seen severely impaired in Lesion‐only rats and fully recovered in Transplanted rats, and appeared partly lost again 2 months after ablation of the implanted neuroblasts. Morphological analyses confirmed the almost total lesion‐induced noradrenergic neuronal and terminal fiber loss, the near‐normal reinnervation of the hippocampus promoted by the transplants, and its complete removal by the second lesion. Notably, the noradrenergic‐rich transplants normalized also the nuclear expression of the transactive response DNA‐binding protein 43 (TDP‐43) in various hippocampal subregions, whose cytoplasmic (i.e., pathological) occurrence appeared dramatically increased as a result of the lesions. Thus, integrity of ascending noradrenergic inputs to the hippocampus may be required for the regulation of specific aspects of learning and memory and to prevent TDP‐43 tissue pathology. [ABSTRACT FROM AUTHOR]

GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Shortterm GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories. [ABSTRACT FROM AUTHOR]

Abstract: Galanin-like peptide (GALP) is located in the arcuate nucleus (Arc) of the hypothalamus and is known to regulate both food intake and sexual behaviors in adult male rats. We have previously demonstrated that ICV GALP administration elicits a significant fos response within the medial preoptic area (mPOA). GALP is known to stimulate both food intake and male-typical sex behavior, presumably by direct actions within the mPOA. Recent data from our and other labs have led us to suspect that GALP effects on sex behaviors are due to activation of incertohypothalamic dopaminergic neurons that terminate within the mPOA. To test the hypothesis that GALP activates mPOA dopaminergic systems, we utilized an immunolesion technique to eliminate dopaminergic fiber input to the mPOA via a dopamine transporter-specific toxin (DATSAP, n =8) and compared to control injections (SAP, n =8). All animals were sexually experienced adult male Long-Evans rats. DATSAP-treated male rats showed a significant (p <0.001) reduction in male sexual behaviors compared to SAP controls. We found that elimination of dopaminergic fibers within the mPOA significantly (p <0.001) eliminated all aspects of male sexual behavior under normal mating paradigms. Injections of GALP (5.0nmol) significantly increased (p <0.01) male sex behavior and food intake in SAP control male rats but GALP did not stimulate the expression of these behaviors in DATSAP-treated rats. The orexigenic and anorexigenic effects of GALP were significantly (p <0.001) attenuated in DATSAP-treated male rats compared to SAP controls; however, ICV GALP was still able to significantly (p <0.05) reduce 24h body weight in both DATSAP and SAP rats. ICV GALP significantly (p <0.05) stimulated fos within the mPOA of SAP rats but not in DATSAP-treated male rats. These data suggest that GALP activates feeding and sexual behaviors in male rats by stimulating dopaminergic neurons that terminate within the mPOA. [Copyright &y& Elsevier]

Glycogen synthase kinase-3β (GSK-3β) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is inhibited by phosphorylation of the Ser9 residue and up-regulated by Tyr216 phosphorylation. Activated GSK-3β increases phosphorylation of tau protein and induces cell death in a variety of cultured neurons, whereas phosphorylation of phosphatidylinositol-3 (PI-3) kinase-dependent protein kinase B (Akt), which inhibits GSK-3β activity, is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192 IgG-saporin was used to address the potential role of GSK-3β in the degeneration of basal forebrain cholinergic neurons, which are preferentially vulnerable in Alzheimer's disease (AD) brain. GSK-3β co-localized with a subset of forebrain cholinergic neurons and loss of these neurons was accompanied by a transient decrease in PI-3 kinase, phospho-Ser473Akt and phospho-Ser9GSK-3β levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus. Total Akt, GSK-3β, tau and phospho-Tyr216GSK-3β levels were not significantly altered in these brain regions in animals treated with 192 IgG-saporin. Systemic administration of the GSK-3β inhibitor LiCl did not significantly affect cholinergic marker or phospho-Ser9GSK-3β levels in control rats but did preclude 192-IgG saporin-induced alterations in PI-3 kinase/phospho-Akt, phospho-Ser9GSK-3β and phospho-tau levels, and also partly protected cholinergic neurons against the immunotoxin. These results provide the first evidence that increased GSK-3β activity, via decreased Ser9 phosphorylation, can mediate, at least in part, 192-IgG saporin-induced in vivo degeneration of forebrain cholinergic neurons by enhancing tau phosphorylation. The partial protection of these neurons following inhibition of GSK-3β kinase activity suggests a possible therapeutic role for GSK-3β inhibitors in attenuating the loss of basal forebrain cholinergic neurons observed in AD. [ABSTRACT FROM AUTHOR]

Tethered crickets flying in a wind tunnel adopt a characteristic posture in which the antennae are pointed in parallel and anteriorly into the headwind. Although the firing rates of antennal motoneurons are largely reduced after the start of a flight sequence, the associated postural changes of the antennae are small. It is hypothesised that proctolin, which is present in antennal motoneurons, stabilises the prolonged antennal forward position. To test this hypothesis, proctolin was blocked by anti-proctolin antiserum injections into one antennal base in otherwise intact behaving crickets. The antiserum quickly led to prolonged backward deflections of the treated antennae in 65% of cases. It then took more than one hour for the deflected posture to revert to a normal flight posture. It appears that proctolin is necessary to produce muscle tension large enough to hold the antennae in a forward position and to compensate for the headwind drag. Proctolin, therefore, acts to generate force with reduced electrical activity of motoneurons and muscles. [ABSTRACT FROM AUTHOR]

Impairments in learning and memory, induced by surgical or excitotoxic lesions of the septo-hippocampal or basalo-cortical pathways, can be ameliorated by grafts of cholinergic-rich foetal basal forebrain tissue into the hippocampus and/or neocortex. However, the effects of such grafts have been only partial, which may be due to the non-specific nature of the lesioning procedures used in these studies, known to destroy both cholinergic and non-cholinergic neuronal projections. In the present study, we have explored the effects of cholinergic-rich grafts in rats subjected to selective cholinergic lesions, induced by intraventricular injections of the immunotoxin 192 IgG-saporin. This lesion, which selectively destroyed 85–95% of the cholinergic neurons in both the septal-diagonal band and nucleus basalis, produced a long-lasting, substantial impairment in both the acquisition of spatial reference memory in the Morris water maze task and delay-dependent short-term memory performance, as seen in a delayed matching-to-position test. Foetal cholinergic grafts (but not control grafts of cerebellar tissue) implanted at multiple sites into both the hippocampus and fronto-parietal neocortex, bilaterally, completely reversed the acquisition deficit in place navigation in the water maze, to an extent that greatly exceeded that previously seen in animals with non-selective lesions. Most notably, however, the impairment in short-term memory was only partially and inconsistently affected, and only at the longest delay times. The morphological analysis, performed at about 7 months after transplantation, showed that the grafts had re-established a close to normal cholinergic innervation in the initially denervated cortical and hippocampal territories. It is proposed that the differential effects of cholinergic-rich transplants on different aspects of cognitive performance may define intrinsic limitations to the functional capacity of the ectopically placed grafts, ... [ABSTRACT FROM AUTHOR]