Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.

Single-cell sequencing methods have emerged as powerful tools for identification of heterogeneous cell types within defined brain regions. Application of single-cell techniques to study the transcriptome of activated neurons can offer insight into molecular dynamics associated with differential neuronal responses to a given experience. Through evaluation of common whole-cell and single-nuclei RNA-sequencing (snRNA-seq) methods, here we show that snRNA-seq faithfully recapitulates transcriptional patterns associated with experience-driven induction of activity, including immediate early genes (IEGs) such as Fos, Arc and Egr1. SnRNA-seq of mouse dentate granule cells reveals large-scale changes in the activated neuronal transcriptome after brief novel environment exposure, including induction of MAPK pathway genes. In addition, we observe a continuum of activation states, revealing a pseudotemporal pattern of activation from gene expression alone. In summary, snRNA-seq of activated neurons enables the examination of gene expression beyond IEGs, allowing for novel insights into neuronal activation patterns in vivo.

In drug addiction, the transition from casual drug use to dependence has been linked to a shift away from positive reinforcement and towards negative reinforcement. That is, drugs ultimately are relied on to prevent or relieve negative states that otherwise result from abstinence (e.g., withdrawal) or from adverse environmental circumstances (e.g., stress). Recent work has suggested that this “dark side” shift also is key in the development of food addiction. Initially, palatable food consumption has both positive reinforcing, pleasurable effects and negative reinforcing, “comforting” effects that can acutely normalize organism responses to stress. Repeated, intermittent intake of palatable food may instead amplify brain stress circuitry and downregulate brain reward pathways such that continued intake becomes obligatory to prevent negative emotional states via negative reinforcement. Stress, anxiety and depressed mood have shown high comorbidity with and the potential to trigger bouts of addiction-like eating behavior in humans. Animal models indicate that repeated, intermittent access to palatable foods can lead to emotional and somatic signs of withdrawal when the food is no longer available, tolerance and dampening of brain reward circuitry, compulsive seeking of palatable food despite potentially aversive consequences, and relapse to palatable food-seeking in response to anxiogenic-like stimuli. The neurocircuitry identified to date in the “dark” side of food addiction qualitatively resembles that associated with drug and alcohol dependence. The present review summarizes Bart Hoebel’s groundbreaking conceptual and empirical contributions to understanding the role of the “dark side” in food addiction along with related work of those that have followed him.