Designer Receptors Enhance Memory in a Mouse Model of Down Syndrome

Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer\u27s disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. Previous studies have shown that LC-enhancing drugs can slow the progression of AD pathology, including amyloid aggregation, oxidative stress, and inflammation. We have shown that LC degeneration in Ts65Dn mice leads to exaggerated memory loss and neuronal degeneration. We used a DREADD, hM3Dq, administered via adeno-associated virus into the LC under a synthetic promoter, PRSx8, to selectively stimulate LC neurons by exogenous administration of the inert DREADD ligand clozapine-N-oxide. DREADD stimulation of LC-NE enhanced performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without significant behavioral effects in controls. To confirm that the noradrenergic transmitter system was responsible for the enhanced memory function, the NE prodrug l-threo-dihydroxyphenylserine was administered in Ts65Dn and normosomic littermate control mice, and produced similar behavioral results. Thus, NE stimulation may prevent memory loss in Ts65Dn mice, and may hold promise for treatment in individuals with DS and dementia

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies

Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.

The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction

Comparison of transplant efficiency between spontaneously derived and noggin-primed human embryonic stem cell neural precursors in the quinolinic acid rat model of Huntington\u27s disease

Human neural precursors (hNP) derived from embryonic stem cells (hESC) may provide a viable cellular source for transplantation therapy for Huntington\u27s disease (HD). However, developing effective transplantation therapy for the central nervous system (CNS) using hESC relies on optimizing the in vitro production of hNP to control appropriate in vivo posttransplantation neuronal differentiation. The current study provides the first direct in vivo comparison of the transplant efficiency and posttransplantation characteristics of spontaneously derived and noggin-primed hNP following transplantation into the quinolinic acid (QA) rat model of HD. We show that spontaneously derived and noggin-primed hNP both survived robustly up to 8 weeks after transplantation into the QA-lesioned striatum of the adult rat. Transplanted hNP underwent extensive migration and large-scale differentiation towards a predominantly neuronal fate by 8 weeks post-transplantation. Furthermore, in vitro noggin priming of hNP specifically increased the extent of neuronal differentiation at both 4 and 8 weeks posttransplantation when compared to spontaneously derived hNP grafts. The results of this study suggest that in vit ro noggin priming provides an effective mechanism by which to enhance hNP transplant efficiency for the treatment of HD

Use of vivo-morpholinos for control of protein expression in the adult rat brain

► Here we test use of vivo-morpholinos for protein suppression in the rat brain. ► We show effective suppression of GLT-1, xCT, and orexin proteins. ► We provide evidence that vivo-morpholinos can be used without evidence of toxicity. ► However, high dose vivo-morpholinos are neurotoxic. Vivo-morpholinos are commercially available morpholino oligomers with a terminal octa-guanidinium dendrimer for enhanced cell-permeability. Existing evidence from systemically delivered vivo-morpholinos indicate that genetic suppression can last from days to weeks without evidence of cellular toxicity. However, intravenously delivered vivo-morpholinos are ineffective at protein suppression in the brain, and no evidence is available regarding whether intracranially delivered vivo-morpholinos effectively reduce target protein levels, or do so without inducing neurotoxicity. Here we report examples in which in vivo microinjection of antisense vivo-morpholinos directed against three different targets (xCT, GLT1, orexin) in two different brain regions resulted in significant suppression of protein expression without neurotoxicity. Expression was significantly suppressed at six to seven days post-administration, but returned to baseline levels within fourteen days. These results indicate that direct intracranial administration of vivo-morpholinos provides an effective means by which to suppress protein expression in the brain for one to two weeks