Yoav Livneh

Sensory Input Enhances Synaptogenesis of Adult-Born Neurons

The adult mammalian brain maintains a prominent stem cell niche in the subventricular zone supplying new neurons to the olfactory bulb. We examined the dynamics of synaptogenesis by imaging the formation and elimination of clusters of a postsynaptic marker (PSD95), genetically targeted to adult-born neurons. We imaged in vivo adult-born periglomerular neurons (PGNs) during two phases of development, immaturity and maturity. Immature PGNs showed high levels of PSD95 puncta dynamics during 12–72 h intervals. Mature PGNs were more stable compared with immature PGNs but still remained dynamic, suggesting that synaptogenesis persists long after these neurons integrated into the network. By combining intrinsic signal and two photon imaging we followed PSD95 puncta in sensory enriched glomeruli. Sensory input upregulated the development of adult-born PGNs only in enriched glomeruli. Our data provide evidence for an activity-based mechanism that enhances synaptogenesis of adult-born PGNs during their initial phases of development.

A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH.

Arcuate nucleus (ARC) neurons sense the fed or fasted state and regulate hunger. Agouti-related protein (AgRP) neurons in the ARC (ARCAgRP neurons) are stimulated by fasting and, once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARCPOMC) neurons are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARCAgRP neurons, ARCPOMC neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified. Here we show that glutamate-releasing ARC neurons expressing oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular hypothalamus (PVHMC4R neurons). Transmission across the ARCGlutamatergic→PVHMC4R synapse is potentiated by the ARCPOMC neuron-derived MC4R agonist, α-melanocyte stimulating hormone (α-MSH). This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides insight into regulation of hunger and satiety.

Experience-dependent plasticity of mature adult-born neurons

The adult olfactory bulb and hippocampus are continuously supplied with newborn neurons that are thought to possess a capacity for plasticity only at a young neuronal age, mainly during the early stages of integration into the network. We find that the two main types of adult-born neurons in the mouse olfactory bulb undergo experience-dependent plasticity long after maturation and integration, as evidenced by stabilization of synaptic turnover rates. Thus, the potential time window for plasticity of adult-born neurons extends well into maturity.

Homeostatic circuits selectively gate food cue responses in insular cortex

Physiological needs bias perception and attention to relevant sensory cues. This process is ‘hijacked’ by drug addiction, causing cue-induced cravings and relapse. Similarly, its dysregulation contributes to failed diets, obesity, and eating disorders. Neuroimaging studies in humans have implicated insular cortex in these phenomena. However, it remains unclear how ‘cognitive’ cortical representations of motivationally relevant cues are biased by subcortical circuits that drive specific motivational states. Here we develop a microprism-based cellular imaging approach to monitor visual cue responses in the insular cortex of behaving mice across hunger states. Insular cortex neurons demonstrate food-cue-biased responses that are abolished during satiety. Unexpectedly, while multiple satiety-related visceral signals converge in insular cortex, chemogenetic activation of hypothalamic ‘hunger neurons’ (expressing agouti-related peptide (AgRP)) bypasses these signals to restore hunger-like response patterns in insular cortex. Circuit mapping and pathway-specific manipulations uncover a pathway from AgRP neurons to insular cortex via the paraventricular thalamus and basolateral amygdala. These results reveal a neural basis for state-specific biased processing of motivationally relevant cues.

MicroRNA Editing Facilitates Immune Elimination of HCMV Infected Cells

The human cytomegalovirus (HCMV) is extremely prevalent in the human population. Infection by HCMV is life threatening in immune compromised individuals and in immune competent individuals it can cause severe birth defects, developmental retardation and is even associated with tumor development. While numerous mechanisms were developed by HCMV to interfere with immune cell activity, much less is known about cellular mechanisms that operate in response to HCMV infection. Here we demonstrate that in response to HCMV infection, the expression of the short form of the RNA editing enzyme ADAR1 (ADAR1-p110) is induced. We identified the specific promoter region responsible for this induction and we show that ADAR1-p110 can edit miR-376a. Accordingly, we demonstrate that the levels of the edited-miR-376a (miR-376a(e)) increase during HCMV infection. Importantly, we show that miR-376a(e) downregulates the immune modulating molecule HLA-E and that this consequently renders HCMV infected cells susceptible to elimination by NK cells.

Long‐term changes in the morphology and synaptic distributions of adult‐born neurons

The adult mammalian olfactory bulb (OB) is continuously supplied with adult‐born neurons. While some new neurons die shortly after arrival into the OB, others persist throughout the life of the animal. Here we followed the long‐term morphological changes in adult‐born periglomerular neurons and granule cells from the mouse OB well after they mature. We present a dataset of dendritic morphology and synaptic distributions from >100 adult‐born neurons as imaged in vivo and reconstructed in 3D. The dataset currently includes a substantial range of neuronal ages (0.5–11 months old). Using this dataset, we show that the morphological steady‐state which adult‐born periglomerular neurons reach soon after maturation is not maintained in older neurons. Rather, total dendritic length decreases after 6 months of age. We find that this morphological decrease in “old” periglomerular neurons is regulated by the age of the animal, and is independent of neuronal age. This suggests that morphological development of adult‐born neurons is regulated extrinsically. Our dendritic morphology dataset of 3D reconstructions is made available to the scientific community so it may serve as a useful resource for comparative morphological studies of the OB, and in particular of adult neurogenesis. J. Comp. Neurol. 519:2212–2224, 2011.

Functional transformations of odor inputs in the mouse olfactory bulb

Sensory inputs from the nasal epithelium to the olfactory bulb (OB) are organized as a discrete map in the glomerular layer (GL). This map is then modulated by distinct types of local neurons and transmitted to higher brain areas via mitral and tufted cells. Little is known about the functional organization of the circuits downstream of glomeruli. We used in vivo two-photon calcium imaging for large scale functional mapping of distinct neuronal populations in the mouse OB, at single cell resolution. Specifically, we imaged odor responses of mitral cells (MCs), tufted cells (TCs) and glomerular interneurons (GL-INs). Mitral cells population activity was heterogeneous and only mildly correlated with the olfactory receptor neuron (ORN) inputs, supporting the view that discrete input maps undergo significant transformations at the output level of the OB. In contrast, population activity profiles of TCs were dense, and highly correlated with the odor inputs in both space and time. Glomerular interneurons were also highly correlated with the ORN inputs, but showed higher activation thresholds suggesting that these neurons are driven by strongly activated glomeruli. Temporally, upon persistent odor exposure, TCs quickly adapted. In contrast, both MCs and GL-INs showed diverse temporal response patterns, suggesting that GL-INs could contribute to the transformations MCs undergo at slow time scales. Our data suggest that sensory odor maps are transformed by TCs and MCs in different ways forming two distinct and parallel information streams.

A Time for Atlases and Atlases for Time

Advances in neuroanatomy and computational power are leading to the construction of new digital brain atlases. Atlases are rising as indispensable tools for comparing anatomical data as well as being stimulators of new hypotheses and experimental designs. Brain atlases describe nervous systems which are inherently plastic and variable. Thus, the levels of brain plasticity and stereotypy would be important to evaluate as limiting factors in the context of static brain atlases. In this review, we discuss the extent of structural changes which neurons undergo over time, and how these changes would impact the static nature of atlases. We describe the anatomical stereotypy between neurons of the same type, highlighting the differences between invertebrates and vertebrates. We review some recent experimental advances in our understanding of anatomical dynamics in adult neural circuits, and how these are modulated by the organisms experience. In this respect, we discuss some analogies between brain atlases and the sequenced genome and the emerging epigenome. We argue that variability and plasticity of neurons are substantially high, and should thus be considered as integral features of high-resolution digital brain atlases.

Gating of visual processing by physiological need

Physiological need states and associated motivational drives can bias visual processing of cues that help meet these needs. Human neuroimaging studies consistently show a hunger-dependent, selective enhancement of responses to images of food in association cortex and amygdala. More recently, cellular-resolution imaging combined with circuit mapping experiments in behaving mice have revealed underlying neuronal population dynamics and enabled tracing of pathways by which hunger circuits influence the assignment of value to visual objects in visual association cortex, insular cortex, and amygdala. These experiments begin to provide a mechanistic understanding of motivation-specific neural processing of need-relevant cues in healthy humans and in disease states such as obesity and other eating disorders.

History-dependent odor processing in the mouse olfactory bulb

In nature, animals normally perceive sensory information on top of backgrounds. Thus, the neural substrate to perceive under background conditions is inherent in all sensory systems. Where and how sensory systems process backgrounds is not fully understood. In olfaction, just a few studies have addressed the issue of odor coding on top of continuous odorous backgrounds. Here, we tested how background odors are encoded by mitral cells (MCs) in the olfactory bulb (OB) of male mice. Using in vivo two-photon calcium imaging, we studied how MCs responded to odors in isolation versus their responses to the same odors on top of continuous backgrounds. We show that MCs adapt to continuous odor presentation and that mixture responses are different when preceded by background. In a subset of odor combinations, this history-dependent processing was useful in helping to identify target odors over background. Other odorous backgrounds were highly dominant such that target odors were completely masked by their presence. Our data are consistent in both low and high odor concentrations and in anesthetized and awake mice. Thus, odor processing in the OB is strongly influenced by the recent history of activity, which could have a powerful impact on how odors are perceived. SIGNIFICANCE STATEMENT We examined a basic feature of sensory processing in the olfactory bulb. Specifically, we measured how mitral cells adapt to continuous background odors and how target odors are encoded on top of such background. Our results show clear differences in odor coding based on the immediate history of the stimulus. Our results support the argument that odor coding in the olfactory bulb depends on the recent history of the sensory environment.