12 months is a pivotal age for olfactory perceptual learning and its underlying neuronal plasticity in aging mice

International audienceNormal brain aging is associated with deficits in cognitive and sensory processes, due to subtle impairment of synaptic contacts and plasticity. Impairment may be discrete in basal conditions but is revealed when cerebral plasticity is involved, such as in learning contexts. We used olfactory perceptual learning, a non-associative form of learning in which discrimination between perceptually similar odorants is improved following exposure to these odorants, to better understand the cellular bases of olfactory aging in mice. We first evaluated learning ability and memory retention in 2-, 6-, 12-, and 18-month-old mice, and identified 12 months as a pivotal age when memory retention subtly declines before learning becomes totally impaired at later ages. We then showed that learning-induced structural plasticity of adult-born granule cells is specific to cells responding to the learned odorants in the olfactory bulb of young adult mice and loses its specificity in 12-month-old mice, in parallel to memory impairment. Taken together, our data refine our understanding of aging-related impairment of plasticity mechanisms in the olfactory bulb and consequent induction of olfactory learning and memory deficits

Opposite regulation of inhibition by adult-born granule cells during implicit versus explicit olfactory learning

Both passive exposure and active learning through reinforcement enhance fine sensory discrimination abilities. In the olfactory system, this enhancement is thought to occur partially through the integration of adult-born inhibitory interneurons resulting in a refinement of the representation of overlapping odorants. Here, we identify in mice a novel and unexpected dissociation between passive and active learning at the level of adult-born granule cells. Specifically, while both passive and active learning processes augment neurogenesis, adult-born cells differ in their morphology, functional coupling and thus their impact on olfactory bulb output. Morphological analysis, optogenetic stimulation of adult-born neurons and mitral cell recordings revealed that passive learning induces increased inhibitory action by adult-born neurons, probably resulting in more sparse and thus less overlapping odor representations. Conversely, after active learning inhibitory action is found to be diminished due to reduced connectivity. In this case, strengthened odor response might underlie enhanced discriminability

Fragile X mental retardation protein regulates olfactory sensitivity but not odorant discrimination

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and is characterized by cognitive impairments and altered sensory function. It is caused by absence of fragile X mental retardation protein (FMRP), an RNA-binding protein essential for normal synaptic plasticity and function. Animal models have provided important insights into mechanisms through which loss of FMRP impacts cognitive and sensory development and function. While FMRP is highly enriched in the developing and adult olfactory bulb (OB), its role in olfactory sensory function remains poorly understood. Here, we used a mouse model of FXS, the fmr1 (-/y) mouse, to test whether loss of FMRP impacts olfactory discrimination, habituation, or sensitivity using a spontaneous olfactory cross-habituation task at a range of odorant concentrations. We demonstrated that fmr1 (-/y) mice have a significant decrease in olfactory sensitivity compared with wild type controls. When we controlled for differences in sensitivity, we found no effect of loss of FMRP on the ability to habituate to or spontaneously discriminate between odorants. These data indicate that loss of FMRP significantly alters olfactory sensitivity, but not other facets of basal olfactory function. These findings have important implications for future studies aimed at understanding the role of FMRP on sensory functioning

Non-imaged based method for matching brains in a common anatomical space for cellular imagery

Cellular imagery using histology sections is one of the most common techniques used in Neuroscience. However, this inescapable technique has severe limitations due to the need to delineate regions of interest on each brain, which is time consuming and variable across experimenters

Functional and anatomical characterization of atrophic age-related macular degeneration in an aged mouse model

Purpose: To develop an animal model of atrophic age-related macular degeneration (aAMD) in aged mice that more closely mimics the natural progression of the disease. Methods: 12- and 18-month-old CBl57/6JRj mice were immunized with murine serum albumin (MSA) conjugated with carboxyethyl pyrrole (CEP). The immunization, given into the hock, was followed by 3 booster injections into the neck over a 3-month period. Immunized mice and age-matched controls were trained for a visual discrimination and an optokinetic response task to determine the objective visual threshold (OVT) at arrival and at 3 months; funduscopy and ocular coherence tomography were performed. After sacrifice, the eyes were enucleated for histological, immunofluorescent and electron microscopy analyses. Results: Retinal imaging confirmed that all mice had normal retinas upon arrival. Three months after mice were immunized the normal retinal age-related alterations were significantly more pronounced in CEP-immunized than in control mice as evidenced by drusenoid alterations, increased retinal thickness, immune activation, signs of retinal degeneration, decreased OVT. Electron microscopy indicated degeneration of the retinal pigment epithelium (RPE). Conclusions: The retinal and behavioral changes in the aged CEP-immunized mice will be useful for the investigation of novel treatments of aAMD. Translational relevance: The enhanced Aged-CEP-Mouse model enables the generation of results highly transferable to human patients and promotes the development of efficient, safe AMD therapies

Neural processing of the reward value of pleasant odorants

International audiencePleasant odorants are represented in the posterior olfactory bulb (pOB) in mice. How does this hedonic information generate odor-motivated behaviors? Using optogenetics, we here report that stimulating the representation of pleasant odorants in a sensory structure, the pOB, can be rewarding, selfmotivating and is accompanied by ventral tegmental area activation. To explore the underlying neural circuitry downstream of the OB, we use 3D high-resolution imaging and optogenetics and determine that the pOB preferentially projects to the olfactory tubercle, whose increased activity is related to odorant attraction. We further show that attractive odorants act as reinforcers in dopamine-dependent place preference learning. Finally, we extend those findings to human, which exhibit place preference learning and an increase BOLD signal in the olfactory tubercle in response to attractive odorants. Thus, strong and persistent attraction induced by some odorants is due to a direct gateway from the pOB to the reward system

Topographical representation of odor hedonics in the olfactory bulb

Hedonic value is a dominant aspect of olfactory perception. Using optogenetic manipulation in freely behaving mice paired with immediate early gene mapping, we demonstrate that hedonic information is represented along the antero-posterior axis of the ventral olfactory bulb. Using this representation, we show that the degree of attractiveness of odors can be bidirectionally modulated by local manipulation of the olfactory bulb's neural networks in freely behaving mice