Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content.

Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.

Transcription factor 4 and its association with psychiatric disorders.

The human transcription factor 4 gene (TCF4) encodes a helix-loop-helix transcription factor widely expressed throughout the body and during neural development. Mutations in TCF4 cause a devastating autism spectrum disorder known as Pitt-Hopkins syndrome, characterized by a range of aberrant phenotypes including severe intellectual disability, absence of speech, delayed cognitive and motor development, and dysmorphic features. Moreover, polymorphisms in TCF4 have been associated with schizophrenia and other psychiatric and neurological conditions. Details about how TCF4 genetic variants are linked to these diseases and the role of TCF4 during neural development are only now beginning to emerge. Here, we provide a comprehensive review of the functions of TCF4 and its protein products at both the cellular and organismic levels, as well as a description of pathophysiological mechanisms associated with this gene.

Peripheral oxytocin injection modulates vomeronasal sensory activity and reduces pup-directed aggression in male mice.

Behaviors are shaped by hormones, which may act either by changing brain circuits or by modifying sensory detection of relevant cues. Pup-directed behaviors have been previously shown to change via action of hormones at the brain level. Here, we investigated hormonal control of pup-induced activity in the vomeronasal organ, an olfactory sensory structure involved in the detection of non-volatile chemosignals. Vomeronasal activity decreases as males switch from a pup-aggressive state to a non-aggressive parenting state, after they socially contact a female. RNA sequencing, qPCR, and in situ hybridization were used to identify expression, in the vomeronasal sensory epithelium, of candidate GPCR hormone receptors chosen by in silico analyses and educated guesses. After identifying that oxytocin and vasopressin receptors are expressed in the vomeronasal organ, we injected the corresponding hormones in mice and showed that oxytocin administration reduced both pup-induced vomeronasal activity and aggressive behavior. Conversely, injection of an oxytocin receptor antagonist in female-primed male animals, which normally exhibit reduced vomeronasal activity, significantly increased the number of active vomeronasal neurons. These data link oxytocin to the modulation of olfactory sensory activity, providing a possible mechanism for changes in male behavior after social experience with females.

From Synapse to Supper: A Food Preference Recipe with Olfactory Synaptic Ingredients.

C1ql3 protein and its receptor Bai3 are involved in synaptic organization and function. In this issue of Neuron, Wang et al. (2020) report that both are essential for synaptic function between the anterior olfactory nucleus and the olfactory bulb and for the generation, but not recall, of associative olfactory memories determining food preference in mice.

The Strange Case of Aggression and the Brain.

Territorial male mice are aggressive toward intruding males, but socially bonded males are not. Through manipulation of activity in a subset of neurons in the ventromedial hypothalamus, Yang et al. (2017) report that social and physiological factors non-linearly interact to control male aggression.

Detection of pup odors by non-canonical adult vomeronasal neurons expressing an odorant receptor gene is influenced by sex and parenting status.

BACKGROUND: Olfaction is a fundamental sense through which most animals perceive the external world. The olfactory system detects odors via specialized sensory organs such as the main olfactory epithelium and the vomeronasal organ. Sensory neurons in these organs use G-protein coupled receptors to detect chemosensory stimuli. The odorant receptor (OR) family is expressed in sensory neurons of the main olfactory epithelium, while the adult vomeronasal organ is thought to express other types of receptors. RESULTS: Here, we describe Olfr692, a member of the OR gene family identified by next-generation RNA sequencing, which is highly upregulated and non-canonically expressed in the vomeronasal organ. We show that neurons expressing this gene are activated by odors emanating from pups. Surprisingly, activity in Olfr692-positive cells is sexually dimorphic, being very low in females. Our results also show that juvenile odors activate a large number of Olfr692 vomeronasal neurons in virgin males, which is correlated with the display of infanticide behavior. . In contrast, activity substantially decreases in parenting males (fathers), where infanticidal aggressive behavior is not frequently observed. CONCLUSIONS: Our results describe, for the first time, a sensory neural population with a specific molecular identity involved in the detection of pup odors. Moreover, it is one of the first reports of a group of sensory neurons the activity of which is sexually dimorphic and depends on social status. Our data suggest that the Olfr692 population is involved in mediating pup-oriented behaviors in mice.

Lack of spatial segregation in the representation of pheromones and kairomones in the mouse medial amygdala.

The nervous system is organized to detect, internally represent and process sensory information to generate appropriate behaviors. Despite the crucial importance of odors that elicit instinctive behaviors, such as pheromones and kairomones, their neural representation remains little characterized in the mammalian brain. Here we used expression of the immediate early gene product c-Fos as a marker of neuronal activity to find that a wide range of pheromones and kairomones produces activation in the medial nucleus of the amygdala, a brain area anatomically connected with the olfactory sensory organs. We see that activity in this nucleus depends on vomeronasal organ input, and that distinct vomeronasal stimuli activate a dispersed ensemble of cells, without any apparent spatial segregation. This activity pattern does not reflect the chemical category of the stimuli, their valence or the induced behaviors. These findings will help build a complete understanding of how odor information is processed in the brain to generate instinctive behaviors.