Gabriel Lepousez

Activation of adult-born neurons facilitates learning and memory

Thousand of local interneurons reach the olfactory bulb of adult rodents every day, but the functional effect of this process remains elusive. By selectively expressing channelrhodopsin in postnatal-born mouse neurons, we found that their activation accelerated difficult odor discrimination learning and improved memory. This amelioration was seen when photoactivation occurred simultaneously with odor presentation, but not when odor delivery lagged by 500 ms. In addition, learning was facilitated when light flashes were delivered at 40 Hz, but not at 10 Hz. Both in vitro and in vivo electrophysiological recordings of mitral cells revealed that 40-Hz stimuli produced enhanced GABAergic inhibition compared with 10-Hz stimulation. Facilitation of learning occurred specifically when photoactivated neurons were generated during adulthood. Taken together, our results demonstrate an immediate causal relationship between the activity of adult-born neurons and the function of the olfactory bulb circuit.

The endocannabinoid system controls food intake via olfactory processes

Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor–dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.

Turnover of Newborn Olfactory Bulb Neurons Optimizes Olfaction

Postdevelopmental neurogenesis occurs in the olfactory bulb (OB), to which new interneurons are continuously recruited. However, only a subset of the adult-generated interneurons survives, as many undergo programmed cell death. As part of homeostatic processes, the removal of new neurons is required alongside the addition of new ones, to ensure a stable neuron number. In addition to a critical role in tissue maintenance, it is still unclear whether this neuronal elimination affects the functioning of adult circuits. Using focal drug delivery restricted to the OB, we investigated the significance of programmed cell death in the adult OB circuits. Cell death was effectively blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD). The zVAD effect differed with newborn interneuron location, either in the superficial (periglomerular cells) or in the deep (granule cells) OB layers. Furthermore, whereas sensory experience potentiated the effect of zVAD on the survival of new granule cells, it had no additional effect on the survival of new periglomerular cells. Thus, distinct mechanisms control the survival/elimination decision of newborn interneuron subtypes. However, zVAD had no effect on the olfactory sensory neurons projecting to the bulb. Remarkably, psychophysical analyzes revealed that a normal rate of new neuron elimination was essential for optimal odorant exploration and discrimination. This study highlights the importance of cell elimination for adjusting olfactory performance. We conclude that adult-generated OB interneurons are continually turned over, rather than simply added, and the precise balance between new and mature interneurons, set through active selection/elimination processes, is essential for optimizing olfaction.

The Impact of Adult Neurogenesis on Olfactory Bulb Circuits and Computations

Modern neuroscience has demonstrated how the adult brain has the ability to profoundly remodel its neurons in response to changes in external stimuli or internal states. However, adult brain plasticity, although possible throughout life, remains restricted mostly to subcellular levels rather than affecting the entire cell. New neurons are continuously generated in only a few areas of the adult brain-the olfactory bulb and the dentate gyrus-where they integrate into already functioning circuitry. In these regions, adult neurogenesis adds another dimension of plasticity that either complements or is redundant to the classical molecular and cellular mechanisms of plasticity. This review extracts clues regarding the contribution of adult-born neurons to the different circuits of the olfactory bulb and specifically how new neurons participate in existing computations and enable new computational functions.

Adult Neurogenesis and the Future of the Rejuvenating Brain Circuits

For a long time, the mammalian brain has been perceived to be a static organ. However, the discovery of adult neurogenesis in most mammalian species, including humans, monkeys, and rodents, has disrupted this view. As this continuous regeneration has an effect on established behavioral patterns, it holds promising therapeutic potential. However, before harnessing this potential regenerative power, we must understand what effects new neurons have on existing brain circuits. Ongoing research contributes to several important steps toward bridging the gap between adult-born neurons, circuits, and behavior. The study of adult neurogenesis in different neurogenic regions from a systems neuroscience perspective will pave the way to understanding how it supports adaptive behavior and why its dysfunction correlates with some human brain disorders.

Odor Discrimination Requires Proper Olfactory Fast Oscillations in Awake Mice

Gamma oscillations are commonly observed in sensory brain structures, notably in the olfactory bulb. The mechanism by which gamma is generated in the awake rodent and its functional significance are still unclear. We combined pharmacological and genetic approaches in the awake mouse olfactory bulb to show that gamma oscillations required the synaptic interplay between excitatory output neurons and inhibitory interneurons. Gamma oscillations were amplified, or abolished, after optogenetic activation or selective lesions to the bulbar output neurons. In response to a moderate increase of the excitation/inhibition ratio in output neurons, long-range gamma synchronization was selectively enhanced while the mean firing activity and the amplitude of inhibitory inputs both remained unchanged in output neurons. This excitation/inhibition imbalance also impaired odor discrimination in an olfactory learning task, suggesting that proper fast neuronal synchronization may be critical for the correct discrimination of similar sensory stimuli.

Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons

Significance The olfactory bulb (OB) receives newly born neurons through adulthood. This process constitutes another means, in addition to molecular or synaptic changes within individual neurons, by which the OB can make changes to its functional circuitry. In this study, we show that adult-born OB neurons display adaptive changes in response to the sensory context. In a restricted domain of the dendritic arbor of adult-born neurons, we found that structural and functional changes are strongest when olfactory cues are associated with a reward. Thus, the recruitment of adult-born neurons should be seen as a form of metaplasticity that strengthens long-range functional connectivity in the olfactory system during learning. The production of new neurons in the olfactory bulb (OB) through adulthood is a major mechanism of structural and functional plasticity underlying learning-induced circuit remodeling. The recruitment of adult-born OB neurons depends not only on sensory input but also on the context in which the olfactory stimulus is received. Among the multiple steps of adult neurogenesis, the integration and survival of adult-born neurons are both strongly influenced by olfactory learning. Conversely, optogenetic stimulation of adult-born neurons has been shown to specifically improve olfactory learning and long-term memory. However, the nature of the circuit and the synaptic mechanisms underlying this reciprocal influence are not yet known. Here, we showed that olfactory learning increases the spine density in a region-restricted manner along the dendritic tree of adult-born granule cells (GCs). Anatomical and electrophysiological analysis of adult-born GCs showed that olfactory learning promotes a remodeling of both excitatory and inhibitory inputs selectively in the deep dendritic domain. Circuit mapping revealed that the malleable dendritic portion of adult-born neurons receives excitatory inputs mostly from the regions of the olfactory cortex that project back to the OB. Finally, selective optogenetic stimulation of olfactory cortical projections to the OB showed that learning strengthens these inputs onto adult-born GCs. We conclude that learning promotes input-specific synaptic plasticity in adult-born neurons, which reinforces the top-down influence from the olfactory cortex to early stages of olfactory information processing.

Adult-Born Neurons in the Olfactory Bulb: Integration and Functional Consequences

The generation of new neurons is sustained throughout life in the olfactory system. In recent years, tremendous progress has been made toward understanding the proliferation, differentiation, migration, and integration of newborn neurons in the olfactory bulb. Here, we discuss recent findings that shed light on different aspects of the integration of adult-born neurons into olfactory circuitry and its significance for behavior.

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.

Doublecortin knockout mice show normal hippocampal-dependent memory despite CA3 lamination defects.

Mutations in the human X-linked doublecortin gene (DCX) cause major neocortical disorganization associated with severe intellectual disability and intractable epilepsy. Although Dcx knockout (KO) mice exhibit normal isocortical development and architecture, they show lamination defects of the hippocampal pyramidal cell layer largely restricted to the CA3 region. Dcx-KO mice also exhibit interneuron abnormalities. As well as the interest of testing their general neurocognitive profile, Dcx-KO mice also provide a relatively unique model to assess the effects of a disorganized CA3 region on learning and memory. Based on its prominent anatomical and physiological features, the CA3 region is believed to contribute to rapid encoding of novel information, formation and storage of arbitrary associations, novelty detection, and short-term memory. We report here that Dcx-KO adult males exhibit remarkably preserved hippocampal- and CA3-dependant cognitive processes using a large battery of classical hippocampus related tests such as the Barnes maze, contextual fear conditioning, paired associate learning and object recognition. In addition, we show that hippocampal adult neurogenesis, in terms of proliferation, survival and differentiation of granule cells, is also remarkably preserved in Dcx-KO mice. In contrast, following social deprivation, Dcx-KO mice exhibit impaired social interaction and reduced aggressive behaviors. In addition, Dcx-KO mice show reduced behavioral lateralization. The Dcx-KO model thus reinforces the association of neuropsychiatric behavioral impairments with mouse models of intellectual disability.