Single cell tracing of Pomc neurons reveals recruitment of 'Ghost' subtypes with atypical identity in a mouse model of obesity.

The hypothalamus contains a remarkable diversity of neurons that orchestrate behavioural and metabolic outputs in a highly plastic manner. Neuronal diversity is key to enabling hypothalamic functions and, according to the neuroscience dogma, it is predetermined during embryonic life. Here, by combining lineage tracing of hypothalamic pro-opiomelanocortin (Pomc) neurons with single-cell profiling approaches in adult male mice, we uncovered subpopulations of 'Ghost' neurons endowed with atypical molecular and functional identity. Compared to 'classical' Pomc neurons, Ghost neurons exhibit negligible Pomc expression and are 'invisible' to available neuroanatomical approaches and promoter-based reporter mice for studying Pomc biology. Ghost neuron numbers augment in diet-induced obese mice, independent of neurogenesis or cell death, but weight loss can reverse this shift. Our work challenges the notion of fixed, developmentally programmed neuronal identities in the mature hypothalamus and highlight the ability of specialised neurons to reversibly adapt their functional identity to adult-onset obesogenic stimuli.

Removal of GABA within adult modulatory systems alters electrical coupling and allows expression of an embryonic-like network.

The maturation and operation of neural networks are known to depend on modulatory neurons. However, whether similar mechanisms may control both adult and developmental plasticity remains poorly investigated. To examine this issue, we have used the lobster stomatogastric nervous system (STNS) to investigate the ontogeny and role of GABAergic modulatory neurons projecting to small pattern generating networks. Using immunocytochemistry, we found that modulatory input neurons to the stomatogastric ganglion (STG) express GABA only after metamorphosis, a time that coincides with the developmental switch from a single to multiple pattern generating networks within the STNS. We demonstrate that blocking GABA synthesis with 3-mercapto-propionic acid within the adult modulatory neurons results in the reconfiguration of the distinct STG networks into a single network that generates a unified embryonic-like motor pattern. Using dye-coupling experiments, we also found that gap-junctional coupling is greater in embryos and GABA-deprived adults exhibiting the unified motor pattern compared with control adults. Furthermore, GABA was found to diminish directly the extent and strength of electrical coupling within adult STG networks. Together, these observations suggest the acquisition of a GABAergic phenotype by modulatory neurons after metamorphosis may induce the reconfiguration of the single embryonic network into multiple adult networks by directly decreasing electrical coupling. The findings also suggest that adult neural networks retain the ability to express typical embryonic characteristics, indicating that network ontogeny can be reversed and that changes in electrical coupling during development may allow the segregation of multiple distinct functional networks from a single large embryonic network.

Maturation of rhythmic neural network: role of central modulatory inputs.

Modulatory systems are well known for their roles in tuning the cellular and synaptic properties in the adult neuronal networks, and play a major role in the control of the flexibility of functional outputs. However far less is known concerning their role in the maturation of neural networks during the development. In this review, using the stomatogastric nervous system of lobster, we will show that the neuromodulatory system exerts a powerful influence on developing neural networks. In the adult the number of both motor target neurons and their modulatory neurons is restricted to tens of identifiable cells. They are therefore well characterized in terms of cellular, synaptic and morphological properties. In the embryo, these target cells and their neuromodulatory population are already present from mid-embryonic life. However, the motor output generated by the system is quite different: while in the embryo all the target neurons are organized into a single network generating unique motor pattern, in the adult this population splits into two distinct networks generating separate patterns. This ontogenetic partitioning does not rely on progressive acquisition of adult properties but rather on a switch between two possible network operations. Indeed, adult networks are present early in the embryonic life but their expression is repressed by central modulatory neurons. Moreover, embryonic networks can be revealed in the adult system again by altering modulatory influences. Therefore, independently of the developmental age, two potential network phenotypes co-exist within the same neuronal architecture: when one is expressed, the other one is hidden and vice versa. These transitions do not necessarily need dramatic changes such as growth/retraction of processes, acquisition of new intra-membrane proteins etc. but rather, as shown by modelling studies, it may simply rely on a subtle tuning of pre-existing intercellular electrical coupling. This in turn suggests that progressive ontogenetic alteration may not take place at the level of the target network but rather at the level of modulatory input neurons.

Electrical coupling can prevent expression of adult-like properties in an embryonic neural circuit.

Electrical coupling is widespread in developing nervous systems and plays a major role in circuit formation and patterning of activity. In most reported cases, such coupling between rhythmogenic neurons tends to synchronize and enhance their oscillatory behavior, thereby producing monophasic rhythmic output. However, in many adult networks, such as those responsible for rhythmic motor behavior, oscillatory neurons are linked by synaptic inhibition to produce rhythmic output with multiple phases. The question then arises whether such networks are still able to generate multiphasic output in the early stage of development when electrical coupling is abundant. A suitable model for addressing this issue is the lobster stomatogastric nervous system (STNS). In the adult animal, the STNS consists of three discrete neural networks that are comprised of oscillatory neurons interconnected by reciprocal inhibition. These networks generate three distinct rhythmic motor patterns with large amplitude neuronal oscillations. By contrast, in the embryo the same neuronal population expresses a single multiphasic rhythm with small-amplitude oscillations. Recent findings have revealed that adult-like network properties are already present early in the embryonic system but are masked by an as yet unknown mechanism. Here we use computer simulation to test whether extensive electrical coupling may be involved in masking adult-like properties in the embryonic STNS. Our basic model consists of three different adult-like STNS networks that are built of relaxation oscillators interconnected by reciprocal synaptic inhibition. Individual model cells generate slow membrane potential oscillations without action potentials. The introduction of widespread electrical coupling between members of these networks dampens oscillation amplitudes and, at moderate coupling strengths, may coordinate neuronal activity into a single rhythm with different phases, which is strongly reminiscent of embryonic STNS output. With a further increase in coupling strength, the system reaches one of two final states depending on the relative contribution of inhibition and inherent oscillatory properties within the networks: either fully synchronized and dampened oscillations, or a complete collapse of activity. Our simulations indicate that, beginning from either of these two states, the emergence of distinct adult networks during maturation may arise from a developmental decrease in electrical coupling that unmasks preexisting adult-like network properties.