Effect of Growth Hormone Secretagogue Receptor Deletion on Growth, Pulsatile Growth Hormone Secretion, and Meal Pattern in Male and Female Mice.

INTRODUCTION: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. METHODS: We assessed the sex-specific contribution of GHS-R1a signaling in the activity of the GH/IGF-1 axis, metabolic parameters, and feeding behavior in adolescent (5-6 weeks old) or adult (10-19 weeks old) GHS-R KO (Ghsr-/-) and WT (Ghsr+/+) male and female mice. RESULTS: Adult Ghsr-/- male and female mice displayed deficits in weight and linear growth that were correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr-/- mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr-/- females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations, or ambulatory activity did not predict differences in GH secretion. DISCUSSION/CONCLUSION: These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occurring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females.

Lower leptin level at discharge in acute anorexia nervosa is associated with early weight-loss.

OBJECTIVE: Predictive values of acute phase metabolic abnormalities of anorexia nervosa (AN) have seldom been studied. As early postrestoration weight loss is associated with poor outcome, discharge biologic parameters were assessed to detect an association with 2-month follow-up weight loss as a proxy to poor outcome. METHOD: Fasting plasma levels of leptin, acyl-ghrelin, obestatin, PYY, oxytocin and BDNF were measured in 26 inpatients, at inclusion, at discharge and 2 months later. A body mass index less than 18 2-month postdischarge was considered a poor outcome. RESULTS: Nineteen patients (73%) had a fair outcome and seven (27%) had a poor one with a mean loss of 0.69 versus 4.54 kg, respectively. Only discharge leptin levels were significantly higher in fair versus poor outcome patients (14.1 vs. 7.0 ng/ml, p = 0.006). The logistic regression model using discharge leptin, acyl-ghrelin, obestatin, oxytocin, PYY and BDNF levels as predictors of outcome disclosed a nearly significant effect of leptin (p < 0.10). Receiver operating characteristic analysis showed 11.9 ng/ml was the best value of threshold. Neither clinical variables differed according to outcome. CONCLUSION: Leptin level may be a biomarker of early weight relapse after acute inpatient treatment of AN. Its clinical usefulness in monitoring care in AN should further be determined.

Is Ghrelin Synthesized in the Central Nervous System?

Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals.

An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome.

Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

Somatostatin contributes to in vivo gamma oscillation modulation and odor discrimination in the olfactory bulb.

Neuropeptides are systematically encountered in local interneurons, but their functional contribution in neural networks is poorly documented. In the mouse main olfactory bulb (MOB), somatostatin is mainly concentrated in local GABAergic interneurons restricted to the external plexiform layer (EPL). Immunohistochemical experiments revealed that the sst2 receptor, the major somatostatin receptor subtype in the telencephalon, is expressed by mitral cells, the MOB principal cells. As odor-activated mitral cells synchronize and generate gamma oscillations of the local field potentials, we investigated whether pharmacological manipulations of sst2 receptors could influence these oscillations in freely behaving mice. In wild-type, but not in sst2 knock-out mice, gamma oscillation power decreased lastingly after intrabulbar injection of an sst2-selective antagonist (BIM-23627), while sst2-selective agonists (octreotide and L-779976) durably increased it. Sst2-mediated oscillation changes were correlated with modifications of the dendrodendritic synaptic transmission between mitral and granule cells. Finally, bilateral injections of BIM-23627 and octreotide respectively decreased and increased odor discrimination performances. Together, these results suggest that endogenous somatostatin, presumably released from EPL interneurons, affects gamma oscillations through the dendrodendritic reciprocal synapse and contributes to olfactory processing. This provides the first direct correlation between synaptic, oscillatory, and perceptual effects induced by an intrinsic neuromodulator.

Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

Ghrelin and obestatin modulate growth hormone-releasing hormone release and synaptic inputs onto growth hormone-releasing hormone neurons.

Ghrelin, a natural ligand of the growth hormone secretagogue receptor (GHS-R), is synthesized in the stomach but may also be expressed in lesser quantity in the hypothalamus where the GHS-R is located on growth hormone-releasing hormone (GHRH) neurons. Obestatin, a peptide derived from the same precursor as ghrelin, is able to antagonize the ghrelin-induced increase of growth hormone (GH) secretion in vivo but not from pituitary explants in vitro. Thus, the blockade of ghrelin-induced GH release by obestatin could be mediated at the hypothalamic level by the neuronal network that controls pituitary GH secretion. Ghrelin increased GHRH and decreased somatostatin (somatotropin-releasing inhibitory factor) release from hypothalamic explants, whereas obestatin only reduced the ghrelin-induced increase of GHRH release, thus indicating that the effect of ghrelin and obestatin is targeted to GHRH neurons. Patch-clamp recordings on mouse GHRH-enhanced green fluorescent protein neurons indicated that ghrelin and obestatin had no significant effects on glutamatergic synaptic transmission. Ghrelin decreased GABAergic synaptic transmission in 44% of the recorded neurons, an effect blocked in the presence of the GHS-R antagonist BIM28163, and stimulated the firing rate of 78% of GHRH neurons. Obestatin blocked the effects of ghrelin by acting on a receptor different from the GHS-R. These data suggest that: (i) ghrelin increases GHRH neuron excitability by increasing their action potential firing rate and decreasing the strength of GABA inhibitory inputs, thereby leading to an enhanced GHRH release; and (ii) obestatin counteracts ghrelin actions. Such interactions on GHRH neurons probably participate in the control of GH secretion.

Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

Is there a hypothalamic basis for anorexia nervosa?

The hypothalamus has long been known to control food intake and energy metabolism through a complex network of primary and secondary neurons and glial cells. Anorexia nervosa being a complex disorder characterized by abnormal feeding behavior and food aversion, it is thus quite surprising that not much is known concerning potential hypothalamic modifications in this disorder. In this chapter, we review the recent advances in the fields of genetics, epigenetics, structural and functional imaging, and brain connectivity, as well as neuroendocrine findings and emerging animal models, which have begun to unravel the importance of hypothalamic adaptive processes to our understanding of the pathology of eating disorders.

Ghrelin Gene Deletion Alters Pulsatile Growth Hormone Secretion in Adult Female Mice.

Using preproghrelin-deficient mice (Ghrl-/-), we previously observed that preproghrelin modulates pulsatile growth hormone (GH) secretion in post-pubertal male mice. However, the role of ghrelin and its derived peptides in the regulation of growth parameters or feeding in females is unknown. We measured pulsatile GH secretion, growth, metabolic parameters and feeding behavior in adult Ghrl-/- and Ghrl+/+ male and female mice. We also assessed GH release from pituitary explants and hypothalamic growth hormone-releasing hormone (GHRH) expression and immunoreactivity. Body weight and body fat mass, linear growth, spontaneous food intake and food intake following a 48-h fast, GH pituitary contents and GH release from pituitary explants ex vivo, fasting glucose and glucose tolerance were not different among adult Ghrl-/- and Ghrl+/+ male or female mice. In vivo, pulsatile GH secretion was decreased, while approximate entropy, that quantified orderliness of secretion, was increased in adult Ghrl-/- females only, defining more irregular GH pattern. The number of neurons immunoreactive for GHRH visualized in the hypothalamic arcuate nucleus was increased in adult Ghrl-/- females, as compared to Ghrl+/+ females, whereas the expression of GHRH was not different amongst groups. Thus, these results point to sex-specific effects of preproghrelin gene deletion on pulsatile GH secretion, but not feeding, growth or metabolic parameters, in adult mice.

Cooperation between hippocampal somatostatin receptor subtypes 4 and 2: functional relevance in interactive memory systems.

The hippocampal somatostatin (sst) receptor subtype 4 (sst(4)) modulates memory formation by diminishing hippocampus-based spatial function while enhancing striatum-dependent behaviors. sst(4)-mediated regulations on neuronal activity in the hippocampus appear to depend on both competitive and cooperative interactions with sst receptor subtype 2 (sst(2)). Here, we investigated whether interactions with sst(2) receptors are required for sst(4)-mediated effects on hippocampus-dependent spatial memory and striatum-dependent cued memory in a water maze paradigm. Competition was assessed in mice by intrahippocampal injections of the sst(4) agonist L-803,087 alone or combined with sst(2) agonists (L-779,976 or octreotide). Effects of L-803,087 were also tested in sst(2) knockout mice to assess for receptor cooperation. Finally, sst(2a) and sst(4) localizations within hippocampal subregions were analyzed by immunohistochemistry and expression levels of sst(2a) and sst(2b) were quantified by real-time qPCR. Hippocampal injections of L-803,087 impaired spatial memory but enhanced cued memory. The latter effect was lost not only in sst(2) knockout mice but also in the presence of sst(2) agonists, whereas the former effect remained unaffected by sst(2) agonists or gene deletion. Octreotide and L-779,976 did not yield memory effects but reduced swim velocity throughout the acquisition trials suggesting that stimulation of sst(2) affected motivation and/or anxiety. sst(2a) and sst(4) were respectively detected in the dentate gyrus (DG) and the CA1 subfield suggesting that their functional interactions are not mediated by direct receptor coupling. Hippocampus sst(2a) expression was 36-fold higher than sst(2b). Possible neural mechanisms and functional significances for interaction between memory systems in relationship with stress-induced changes in hippocampal functions are discussed.

Effects of octreotide exposure during pregnancy in acromegaly.

BACKGROUND: Only six women who were treated with somatostatin analogues (SSAs) throughout their pregnancies have been described so far. The influence of SSAs on the course of pregnancy and newborn outcomes remains largely unknown. Many aspects of SSAs pharmacokinetics in mother and foetus have not yet been defined. METHODS AND FINDINGS: We report a case study on the effects of octreotide on uterine artery blood flow, octreotide concentrations in biological fluids of mother and newborn, and somatostatin (SST) receptor expression and binding at the level of the maternal-foetal barrier tissues in an acromegalic woman treated with short-acting octreotide throughout her pregnancy. An acute decrease in uterine artery blood flow was observed after octreotide injections, without affecting the pregnancy course, delivery, or foetal development. Octreotide concentrations were high in maternal serum and colostrum and lower in umbilical cord serum, amniotic fluid, and newborn serum. All SST receptor subtypes can be expressed in placental tissue but their binding profile was weak both in the placenta and umbilical cord. The child was healthy and developed normally up to age 6 from an anthropometric, metabolic, and endocrine point of view. We reviewed all published reports on pregnancy SSA exposure and outcomes were compared to a time-matched group of acromegalic women not exposed to SSA. No significant effect on the mother or foetus was observed. CONCLUSIONS: Short-acting octreotide appears not to affect the function of the maternal-foetal barrier or foetal development, except for the occurrence of acute, reversible, and clinically irrelevant haemodynamic changes. These data support the feasibility and safety of treatment with short-acting octreotide in acromegalic women during pregnancy and excludes major matters of concern about the effects of this medication on pregnancy itself and its outcome.

Mini-review: Aging of the neuroendocrine system: Insights from nonhuman primate models.

The neuroendocrine system (NES) plays a crucial role in synchronizing the physiology and behavior of the whole organism in response to environmental constraints. The NES consists of a hypothalamic-pituitary-target organ axis that acts in coordination to regulate growth, reproduction, stress and basal metabolism. The growth (or somatotropic), hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes are therefore finely tuned by the hypothalamus through the successive release of hypothalamic and pituitary hormones to control the downstream physiological functions. These functions rely on a complex set of mechanisms requiring tight synchronization between peripheral organs and the hypothalamic-pituitary complex, whose functionality can be altered during aging. Here, we review the results of research on the effects of aging on the NES of nonhuman primate (NHP) species in wild and captive conditions. A focus on the age-related dysregulation of the master circadian pacemaker, which, in turn, alters the synchronization of the NES with the organism environment, is proposed. Finally, practical and ethical considerations of using NHP models to test the effects of nutrition-based or hormonal treatments to combat the deterioration of the NES are discussed.

Unexpected Association of Desacyl-Ghrelin with Physical Activity and Chronic Food Restriction: A Translational Study on Anorexia Nervosa.

Anorexia nervosa (AN) is a severe metabopsychiatric disorder characterised by caloric intake restriction and often excessive physical exercise. Our aim is to assess in female AN patients and in a rodent model, the co-evolution of physical activity and potential dysregulation of acyl-(AG) and desacyl-(DAG) ghrelin plasma concentrations during denutrition and weight recovery. AN inpatients were evaluated at inclusion (T0, n = 29), half-(T1) and total (T2) weight recovery, and one month after discharge (T3, n = 13). C57/Bl6 mice with access to a running wheel, were fed ad libitum or submitted to short-(15 days) or long-(50 days) term quantitative food restriction, followed by refeeding (20 days). In AN patients, AG and DAG rapidly decreased during weight recovery (T0 to T2), AG increased significantly one-month post discharge (T3), but only DAG plasma concentrations at T3 correlated negatively with BMI and positively with physical activity. In mice, AG and DAG both increased during short- and long-term food restriction. After 20 days of ad libitum feeding, DAG was associated to persistence of exercise alteration. The positive association of DAG with physical activity during caloric restriction and after weight recovery questions its role in the adaptation mechanisms to energy deprivation that need to be considered in recovery process in AN.

Resistance to lean mass gain in constitutional thinness in free-living conditions is not overpassed by overfeeding.

BACKGROUND: Constitutional thinness (CT), a non-malnourished underweight state with no eating disorders, is characterized by weight gain resistance to high fat diet. Data issued from muscle biopsies suggested blunted anabolic mechanisms in free-living state. Weight and metabolic responses to protein caloric supplementation has not been yet explored in CT. METHODS: A 2 week overfeeding (additional 600 kcal, 30 g protein, 72 g carbohydrate, and 21 g fat) was performed to compare two groups of CTs (12 women and 11 men) to normal-weight controls (12 women and 10 men). Bodyweight, food intake, energy expenditure, body composition, nitrogen balance, appetite hormones profiles, and urine metabolome were monitored before and after overfeeding. RESULTS: Before overfeeding, positive energy gap was found in both CT genders (309 ± 370 kcal in CT-F and 332 ± 709 kcal in CT-M) associated with higher relative protein intake per kilo (1.74 ± 0.32 g/kg/day in CT-F vs. 1.16 ± 0.23 in C-F, P < 0.0001; 1.56 ± 0.36 in CT-M vs. 1.22 ± 0.32 in C-M, P = 0.03), lower nitrogen (7.26 ± 2.36 g/day in CT-F vs. 11.41 ± 3.64 in C-F, P = 0.003; 9.70 ± 3.85 in CT-M vs. 14.14 ± 4.19 in C-M, P = 0.02), but higher essential amino acids urinary excretion (CT/C fold change of 1.13 for leucine and 1.14 for arginine) in free-living conditions. After overfeeding, CTs presented an accentuated positive energy gap, still higher than in controls (675 ± 540 in CTs vs. 379 ± 427 in C, P = 0.04). Increase in lean mass was induced in both controls genders but not in CTs (a trend was noticed in CT women), despite a similar nitrogen balance after overfeeding (5.06 ± 4.33 g/day in CTs vs. 4.28 ± 3.15 in controls, P = 0.49). Higher anorectic gut hormones' tone, glucagon-like peptide 1 and peptide tyrosine tyrosine, during test meal and higher snacking frequency were noticed before and after overfeeding in CTs. CONCLUSIONS: The blunted muscle energy mechanism, previously described in CTs in free-living state, is associated with basal saturated protein turn over suggested by the concordance of positive nitrogen balance and an increased urine excretion of several essential amino acids. This saturation cannot be overpassed by increasing this spontaneous high-protein intake suggesting a resistance to lean mass gain in CT phenotype.

LSP5-2157 a new inhibitor of vesicular glutamate transporters.

Vesicular glutamate transporters (VGLUT1-3) mediate the uptake of glutamate into synaptic vesicles. VGLUTs are pivotal actors of excitatory transmission and of almost all brain functions. Their implication in various pathologies has been clearly documented. Despite their functional importance, the pharmacology of VGLUTs is limited to a few dyes such as Trypan Blue, Rose Bengal or Brilliant Yellow type. Here, we report the design and evaluation of new potent analogs based on Trypan Blue scaffold. Our best compound, named LSP5-2157, has an EC50 of 50 nM on glutamate vesicular uptake. Using a 3D homology model of VGLUT1 and docking experiments, we determined its putative binding subdomains within vesicular glutamate transporters and validated the structural requirement for VGLUT inhibition. To better estimate the specificity and potency of LSP5-2157, we also investigated its ability to block glutamatergic transmission in autaptic hippocampal cells. Neither glutamate receptors nor GABAergic transmission or transmission machinery were affected by LSP5-2157. Low doses of compound reversibly reduce glutamatergic neurotransmission in hippocampal autpases. LSP5-2157 had a low and depressing effect on synaptic efficacy in hippocampal slice. Furthermore, LSP5-2157 had no effect on NMDA-R- mediated fEPSP but reduce synaptic plasticity induced by 3 trains of 100 Hz. Finally, LSP5-2157 had the capacity to inhibit VGLUT3-dependent auditory synaptic transmission in the guinea pig cochlea. In this model, it abolished the compound action potential of auditory nerve at high concentration showing the limited permeation of LSP5-2157 in an in-vivo model. In summary, the new ligand LSP5-2157, has a high affinity and specificity for VGLUTs and shows some permeability in isolated neuron, tissue preparations or in vivo in the auditory system. These findings broaden the field of VGLUTs inhibitors and open the way to their use to assess glutamatergic functions in vitro and in vivo.

Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature.

The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synthetic molecules endowed with GH release properties. As shown recently through in vitro means, this receptor displays a constitutive activity whose clinical relevance is unknown. Although pharmacological studies have demonstrated that its endogenous ligand--ghrelin--stimulates, through the GHSR, GH secretion and appetite, the physiological importance of the GHSR-dependent pathways remains an open question that gives rise to much controversy. We report the identification of a GHSR missense mutation that segregates with short stature within 2 unrelated families. This mutation, which results in decreased cell-surface expression of the receptor, selectively impairs the constitutive activity of the GHSR, while preserving its ability to respond to ghrelin. This first description, to our knowledge, of a functionally significant GHSR mutation, which unveils the critical importance of the GHSR-associated constitutive activity, discloses an unusual pathogenic mechanism of growth failure in humans.

Ghrelin/obestatin ratio in two populations with low bodyweight: constitutional thinness and anorexia nervosa.

Constitutional thinness (CT) and anorexia nervosa (AN) are two categories of severely underweight subjects. Some appetite-regulating hormones display opposite levels in AN and CT. While levels of ghrelin, an orexigenic hormone, fit with the normal food intake in CT, the lack of efficacy of increased ghrelin levels in AN is not clear. Obestatin is a recently described peptide derived from the preproghrelin gene, reported to inhibit appetite in contrast to ghrelin. The aim of this study was to determine whether the circadian profile of obestatin, total and acylated ghrelin levels is different in CT subjects when compared with AN patients. Six-points circadian profiles of plasma obestatin, acylated ghrelin, total ghrelin and other hormonal and nutritional parameters were evaluated in four groups of young women: 10 CT, 15 restricting-type AN, 7 restored from AN and 9 control subjects. Obestatin circadian levels were significantly higher in AN (p<0.0001) while no difference was found between CT and control subjects. Acylated and total ghrelin were found increased in AN. Acylated ghrelin/obestatin and total ghrelin/obestatin were found decreased in AN compared to CT or C subjects (p<0.05). The percentage of acylated ghrelin was found decreased in CT group (p<0.05). The decreased ghrelin/obestatin ratio found in AN might participate in the restraint in nutriment intake of these patients. In contrast, in CT a lower percentage of acylated over total ghrelin might be considered in the aetiology of this condition.

Strengths and Weaknesses of the Gray Mouse Lemur (Microcebus murinus) as a Model for the Behavioral and Psychological Symptoms and Neuropsychiatric Symptoms of Dementia.

To face the load of the prevalence of Alzheimer's disease in the aging population, there is an urgent need to develop more translatable animal models with similarities to humans in both the symptomatology and physiopathology of dementia. Due to their close evolutionary similarity to humans, non-human primates (NHPs) are of primary interest. Of the NHPs, to date, the gray mouse lemur (Microcebus murinus) has shown promising evidence of its translatability to humans. The present review reports the known advantages and limitations of using this species at all levels of investigation in the context of neuropsychiatric conditions. In this easily bred Malagasy primate with a relatively short life span (approximately 12 years), age-related cognitive decline, amyloid angiopathy, and risk factors (i.e., glucoregulatory imbalance) are congruent with those observed in humans. More specifically, analogous behavioral and psychological symptoms and neuropsychiatric symptoms of dementia (BPSD/NPS) to those in humans can be found in the aging mouse lemur. Aged mouse lemurs show typical age-related alterations of locomotor activity daily rhythms such as decreased rhythm amplitude, increased fragmentation, and increased activity during the resting-sleeping phase of the day and desynchronization with the light-dark cycle. In addition, sleep deprivation successfully induces cognitive deficits in adult mouse lemurs, and the effectiveness of approved cognitive enhancers such as acetylcholinesterase inhibitors or N-methyl-D-aspartate antagonists is demonstrated in sleep-deprived animals. This result supports the translational potential of this animal model, especially for unraveling the mechanisms underlying dementia and for developing novel therapeutics to prevent age-associated cognitive decline. In conclusion, actual knowledge of BPSD/NPS-like symptoms of age-related cognitive deficits in the gray mouse lemur and the recent demonstration of the similarity of these symptoms with those seen in humans offer promising new ways of investigating both the prevention and treatment of pathological aging.