High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

An analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats.

The hypothalamic neuropeptide oxytocin (OT) exerts prominent analgesic effects via central and peripheral action. However, the precise analgesic pathways recruited by OT are largely elusive. Here we discovered a subset of OT neurons whose projections preferentially terminate on OT receptor (OTR)-expressing neurons in the ventrolateral periaqueductal gray (vlPAG). Using a newly generated line of transgenic rats (OTR-IRES-Cre), we determined that most of the vlPAG OTR expressing cells targeted by OT projections are GABAergic. Ex vivo stimulation of parvocellular OT axons in the vlPAG induced local OT release, as measured with OT sensor GRAB. In vivo, optogenetically-evoked axonal OT release in the vlPAG of as well as chemogenetic activation of OTR vlPAG neurons resulted in a long-lasting increase of vlPAG neuronal activity. This lead to an indirect suppression of sensory neuron activity in the spinal cord and strong analgesia in both female and male rats. Altogether, we describe an OT-vlPAG-spinal cord circuit that is critical for analgesia in both inflammatory and neuropathic pain models.

Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, obesity, developmental delay and intellectual disability. Studies suggest dysfunctional signaling of the neuropeptide oxytocin as one of the key mechanisms in PWS, and administration of oxytocin via intranasal or systemic routes yielded promising results in both humans and mouse models. However, a detailed assessment of the oxytocin system in mouse models of PWS such as the Magel2-deficient Magel2tm1.Stw mouse, is lacking. In the present study, we performed an automated counting of oxytocin cells in the entire paraventricular nucleus of the hypothalamus of Magel2tm1.Stw and wild-type control mice and found a significant reduction in the caudal part, which represents the parvocellular subdivision. In addition, based on the recent discovery that some astrocytes express the oxytocin receptor (OTR), we performed detailed analysis of astrocyte numbers and morphology in various brain regions, and assessed expression levels of the astrocyte marker glial fibrillary acidic protein, which was significantly decreased in the hypothalamus, but not other brain regions in Magel2tm1.Stw mice. Finally, we analyzed the number of OTR-expressing astrocytes in various brain regions and found a significant reduction in the nucleus accumbens of Magel2tm1.Stw mice, as well as a sex-specific difference in the lateral septum. This study suggests a role for caudal paraventricular nucleus oxytocin neurons as well as OTR-expressing astrocytes in a mouse model of PWS, provides novel information about sex-specific expression of astrocytic OTRs, and presents several new brain regions containing OTR-expressing astrocytes in the mouse brain.

Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors.

Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social behavior among other functions. Several experiments have shown that OT modulates neuronal activity in many brain areas, including sensory cortices. OT neurons thus project axons to various cortical and subcortical structures and activate neuronal subpopulations to increase the signal-to-noise ratio, and in turn, increases the saliency of social stimuli. Less is known about the origin of inputs to OT neurons, but recent studies show that cells projecting to OT neurons are often located in regions where the OT receptor (OTR) is expressed. Thus, we propose the existence of reciprocal connectivity between OT neurons and extrahypothalamic OTR neurons to tune OT neuron activity depending on the behavioral context. Furthermore, the latest studies have shown that OTR-expressing neurons located in social brain regions also project to other social brain regions containing OTR-expressing neurons. We hypothesize that OTR-expressing neurons across the brain constitute a common network coordinated by OT.

The centrifugal visual system of a palaeognathous bird, the Chilean Tinamou (Nothoprocta perdicaria).

The avian centrifugal visual system, which projects from the brain to the retina, has been intensively studied in several Neognathous birds that have a distinct isthmo-optic nucleus (ION). However, birds of the order Palaeognathae seem to lack a proper ION in histologically stained brain sections. We had previously reported in the palaeognathous Chilean Tinamou (Nothoprocta perdicaria) that intraocular injections of Cholera Toxin B subunit retrogradely label a considerable number of neurons, which form a diffuse isthmo-optic complex (IOC). In order to better understand how this IOC-based centrifugal visual system is organized, we have studied its major components by means of in vivo and in vitro tracing experiments. Our results show that the IOC, though structurally less organized than an ION, possesses a dense core region consisting of multipolar neurons. It receives afferents from neurons in L10a of the optic tectum, which are distributed with a wider interneuronal spacing than in Neognathae. The tecto-IOC terminals are delicate and divergent, unlike the prominent convergent tecto-ION terminals in Neognathae. The centrifugal IOC terminals in the retina are exclusively divergent, resembling the terminals from "ectopic" centrifugal neurons in Neognathae. We conclude that the Tinamou's IOC participates in a comparable general IOC-retina-TeO-IOC circuitry as the neognathous ION. However, the connections between the components are structurally different and their divergent character suggests a lower spatial resolution. Our findings call for further comparative studies in a broad range of species for advancing our understanding of the evolution, plasticity and functional roles of the avian centrifugal visual system.

A novel relay nucleus between the inferior colliculus and the optic tectum in the chicken (Gallus gallus).

Processing multimodal sensory information is vital for behaving animals in many contexts. The barn owl, an auditory specialist, is a classic model for studying multisensory integration. In the barn owl, spatial auditory information is conveyed to the optic tectum (TeO) by a direct projection from the external nucleus of the inferior colliculus (ICX). In contrast, evidence of an integration of visual and auditory information in auditory generalist avian species is completely lacking. In particular, it is not known whether in auditory generalist species the ICX projects to the TeO at all. Here we use various retrograde and anterograde tracing techniques both in vivo and in vitro, intracellular fillings of neurons in vitro, and whole-cell patch recordings to characterize the connectivity between ICX and TeO in the chicken. We found that there is a direct projection from ICX to the TeO in the chicken, although this is small and only to the deeper layers (layers 13-15) of the TeO. However, we found a relay area interposed among the IC, the TeO, and the isthmic complex that receives strong synaptic input from the ICX and projects broadly upon the intermediate and deep layers of the TeO. This area is an external portion of the formatio reticularis lateralis (FRLx). In addition to the projection to the TeO, cells in FRLx send, via collaterals, descending projections through tectopontine-tectoreticular pathways. This newly described connection from the inferior colliculus to the TeO provides a solid basis for visual-auditory integration in an auditory generalist bird. J. Comp. Neurol. 525:513-534, 2017. © 2016 Wiley Periodicals, Inc.

An Epigenetic Perspective on the Midwife Toad Experiments of Paul Kammerer (1880-1926).

Paul Kammerer was the most outstanding neo-Lamarckian experimentalist of the early 20th century. He reported spectacular results in the midwife toad, including crosses of environmentally modified toads with normal toads, where acquired traits were inherited in Mendelian fashion. Accusations of fraud generated a great scandal, ending with Kammerer's suicide. Controversy reignited in the 1970s, when journalist Arthur Koestler argued against these accusations. Since then, others have argued that Kammerer's results, even if real, were not groundbreaking and could be explained by somatic plasticity, inadvertent selection, or conventional genetics. More recently, epigenetics has uncovered mechanisms by which inheritance can respond directly to environmental change, inviting a reanalysis of Kammerer's descriptions. Previous arguments for mere somatic plasticity have ignored the description of experiments showing heritable germ line modification. Alleged inadvertent selection associated with egg mortality can be discarded, since mortality decreased in a single generation, upon repeated exposures. The challenging implications did not escape the attention of Kammerer's noted contemporary, William Bateson, but he reacted with disbelief, thus encouraging fraud accusations. Nowadays, formerly puzzling phenomena can be explained by epigenetic mechanisms. Importantly, Kammerer described parent-of-origin effects, an effect of parental sex on dominance. Epigenetic mechanisms underlie these effects in genomic imprinting and experiments of transgenerational epigenetic inheritance. In the early 20th century, researchers had no reason to link them with the inheritance of acquired traits. Thus, the parent-of-origin effects in Kammerer's experiments specifically suggest authenticity. Ultimate proof should come from renewed experimentation. To encourage further research, we present a model of possible epigenetic mechanisms.

Congruent representation of visual and acoustic space in the superior colliculus of the echolocating bat Phyllostomus discolor.

The midbrain superior colliculus (SC) commonly features a retinotopic representation of visual space in its superficial layers, which is congruent with maps formed by multisensory neurons and motor neurons in its deep layers. Information flow between layers is suggested to enable the SC to mediate goal-directed orienting movements. While most mammals strongly rely on vision for orienting, some species such as echolocating bats have developed alternative strategies, which raises the question how sensory maps are organized in these animals. We probed the visual system of the echolocating bat Phyllostomus discolor and found that binocular high acuity vision is frontally oriented and thus aligned with the biosonar system, whereas monocular visual fields cover a large area of peripheral space. For the first time in echolocating bats, we could show that in contrast with other mammals, visual processing is restricted to the superficial layers of the SC. The topographic representation of visual space, however, followed the general mammalian pattern. In addition, we found a clear topographic representation of sound azimuth in the deeper collicular layers, which was congruent with the superficial visual space map and with a previously documented map of orienting movements. Especially for bats navigating at high speed in densely structured environments, it is vitally important to transfer and coordinate spatial information between sensors and motor systems. Here, we demonstrate first evidence for the existence of congruent maps of sensory space in the bat SC that might serve to generate a unified representation of the environment to guide motor actions.

The visual system of a palaeognathous bird: visual field, retinal topography and retino-central connections in the Chilean tinamou (Nothoprocta perdicaria).

Most systematic studies of the avian visual system have focused on Neognathous species, leaving virtually unexplored the Palaeognathae, comprised of the flightless ratites and the South American tinamous. We investigated the visual field, the retinal topography, and the pattern of retinal and centrifugal projections in the Chilean tinamou, a small Palaeognath of the family Tinamidae. The tinamou has a panoramic visual field with a small frontal binocular overlap of 20°. The retina possesses three distinct topographic specializations: a horizontal visual streak, a dorsotemporal area, and an area centralis with a shallow fovea. The maximum ganglion cell density is 61,900/ mm(2) , comparable to Falconiformes. This would provide a maximal visual acuity of 14.0 cycles/degree, in spite of relatively small eyes. The central retinal projections generally conform to the characteristic arrangement observed in Neognathae, with well-differentiated contralateral targets and very few ipsilateral fibers. The centrifugal visual system is composed of a considerable number of multipolar centrifugal neurons, resembling the "ectopic" neurons described in Neognathae. They form a diffuse nuclear structure, which may correspond to the ancestral condition shared with other sauropsids. A notable feature is the presence of terminals in deep tectal layers 11-13. These fibers may represent either a novel retinotectal pathway or collateral branches from centrifugal neurons projecting to the retina. Both types of connections have been described in chicken embryos. Our results widen the basis for comparative studies of the vertebrate visual system, stressing the conserved character of the visual projections' pattern within the avian clade.