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Brain, Behavior and Evolution 2022The amygdala, a complex array of nuclei in the forebrain, controls emotions and emotion-related behaviors in vertebrates. Current research aims to understand the... (Review)
Review
The amygdala, a complex array of nuclei in the forebrain, controls emotions and emotion-related behaviors in vertebrates. Current research aims to understand the amygdala's evolution in ray-finned fish such as zebrafish because of the region's relevance for social behavior and human psychiatric disorders. Clear-cut molecular definitions of the amygdala and its evolutionary-developmental relationship to the one of mammals are critical for zebrafish models of affective disorders and autism. In this review, I argue that the prosomeric model and a focus on the olfactory system's organization provide ideal tools for discovering deep ancestral relationships between the emotional systems of zebrafish and mammals. The review's focus is on the "extended amygdala," which refers to subpallial amygdaloid territories including the central (autonomic) and the medial (olfactory) amygdala required for reproductive and social behaviors. Amphibians, sauropsids, and lungfish share many characteristics with the basic amygdala ground plan of mammals, as molecular and hodological studies have shown. Further exploration of the evolution of the amygdala in basally derived fish vertebrates requires researchers to test these "tetrapod-based" concepts. Historically, this has been a daunting task because the forebrains of basally derived fish vertebrates look very different from those of more familiar tetrapod ones. An extreme case are ray-finned fish (Actinopterygii) like zebrafish because their telencephalon develops through a distinct outward-growing process called eversion. To this day, scientists have struggled to determine how the everted telencephalon compares to non-actinopterygian vertebrates. Using the teleost zebrafish as a genetic model, comparative neurologists began to establish quantifiable molecular definitions that allow direct comparisons between ray-finned fish and tetrapods. In this review, I discuss how the most recent discovery of the zebrafish amygdala ground plan offers an opportunity to identify the developmental constraints of amygdala evolution and function. In addition, I explain how the zebrafish prethalamic eminence (PThE) topologically relates to the medial amygdala proper and the nucleus of the lateral olfactory tract (nLOT). In fact, I consider these previously misinterpreted olfactory structures the most critical missing evolutionary links between actinopterygian and tetrapod amygdalae. In this context, I will also explain why recognizing both the PThE and the nLOT is crucial to understanding the telencephalon eversion. Recognizing these anatomical hallmarks allows direct comparisons of the amygdalae of zebrafish and mammals. Ultimately, the new concepts of the zebrafish amygdala will overcome current dogmas and reach a holistic understanding of amygdala circuits of cognition and emotion in actinopterygians.
Topics: Humans; Animals; Zebrafish; Fishes; Telencephalon; Amygdala; Prosencephalon; Mammals
PubMed: 35760049
DOI: 10.1159/000525669 -
Stem Cell Research & Therapy Apr 2023The first human brain organoid protocol was presented in the beginning of the previous decade, and since then, the field witnessed the development of many new brain...
BACKGROUND
The first human brain organoid protocol was presented in the beginning of the previous decade, and since then, the field witnessed the development of many new brain region-specific models, and subsequent protocol adaptations and modifications. The vast amount of data available on brain organoid technology may be overwhelming for scientists new to the field and consequently decrease its accessibility. Here, we aimed at providing a practical guide for new researchers in the field by systematically reviewing human brain organoid publications.
METHODS
Articles published between 2010 and 2020 were selected and categorised for brain organoid applications. Those describing neurodevelopmental studies or protocols for novel organoid models were further analysed for culture duration of the brain organoids, protocol comparisons of key aspects of organoid generation, and performed functional characterisation assays. We then summarised the approaches taken for different models and analysed the application of small molecules and growth factors used to achieve organoid regionalisation. Finally, we analysed articles for organoid cell type compositions, the reported time points per cell type, and for immunofluorescence markers used to characterise different cell types.
RESULTS
Calcium imaging and patch clamp analysis were the most frequently used neuronal activity assays in brain organoids. Neural activity was shown in all analysed models, yet network activity was age, model, and assay dependent. Induction of dorsal forebrain organoids was primarily achieved through combined (dual) SMAD and Wnt signalling inhibition. Ventral forebrain organoid induction was performed with dual SMAD and Wnt signalling inhibition, together with additional activation of the Shh pathway. Cerebral organoids and dorsal forebrain model presented the most cell types between days 35 and 60. At 84 days, dorsal forebrain organoids contain astrocytes and potentially oligodendrocytes. Immunofluorescence analysis showed cell type-specific application of non-exclusive markers for multiple cell types.
CONCLUSIONS
We provide an easily accessible overview of human brain organoid cultures, which may help those working with brain organoids to define their choice of model, culture time, functional assay, differentiation, and characterisation strategies.
Topics: Humans; Brain; Organoids; Prosencephalon; Induced Pluripotent Stem Cells; Neurons; Cell Differentiation
PubMed: 37061699
DOI: 10.1186/s13287-023-03302-x -
Proceedings of the National Academy of... Apr 2023The internal state of an animal, including homeostatic requirements, modulates its behavior. Negative energy balance stimulates hunger, thus promoting a range of actions...
The internal state of an animal, including homeostatic requirements, modulates its behavior. Negative energy balance stimulates hunger, thus promoting a range of actions aimed at obtaining food. While these survival actions are well established, the influence of the energy status on prosocial behavior remains unexplored. We developed a paradigm to assess helping behavior in which a free mouse was faced with a conspecific trapped in a restrainer. We measured the willingness of the free mouse to liberate the confined mouse under diverse metabolic conditions. Around 42% of ad libitum-fed mice exhibited a helping behavior, as evidenced by the reduction in the latencies to release the trapped cagemate. This behavior was independent of subsequent social contact reward and was associated with changes in corticosterone indicative of emotional contagion. This decision-making process was coupled with reduced blood glucose excursions and higher Adenosine triphosphate (ATP):Adenosine diphosphate (ADP) ratios in the forebrain of helper mice, suggesting that it was a highly energy-demanding process. Interestingly, chronic (food restriction and type 2 diabetes) and acute (chemogenetic activation of hunger-promoting AgRP neurons) situations mimicking organismal negative energy balance and enhanced appetite attenuated helping behavior toward a distressed conspecific. To investigate similar effects in humans, we estimated the influence of glycated hemoglobin (a surrogate of long-term glycemic control) on prosocial behavior (namely charity donation) using the Understanding Society dataset. Our results evidenced that organismal energy status markedly influences helping behavior and that hypothalamic AgRP neurons are at the interface of metabolism and prosocial behavior.
Topics: Energy Metabolism; Helping Behavior; Animals; Mice; Blood Glucose; Adenosine Triphosphate; Adenosine Diphosphate; Prosencephalon; Hunger; Glycated Hemoglobin; Hypothalamus; Glycemic Control; Mice, Inbred C57BL; Male; Humans; Charities; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Streptozocin
PubMed: 37023123
DOI: 10.1073/pnas.2218142120 -
Cell Reports Methods Sep 2022It is known that the human cellular models of Alzheimer's disease (AD) and tauopathy can only recapitulate the very early stage of the disease. To overcome these...
It is known that the human cellular models of Alzheimer's disease (AD) and tauopathy can only recapitulate the very early stage of the disease. To overcome these limitations, we developed a technology to make forebrain organoids (FBOs) from feeder-free induced pluripotent stem cells (iPSC)s by regulating a FGF2 concentration and applied this method to generate FBOs from patients with familial AD (fAD FBOs). The obtained fAD FBOs recapitulated the amyloid-β pathology and increased tau phosphorylation but not tau aggregates. To fully induce the tau pathology, FBOs were injected with adeno-associated virus (AAV)-expressing P301L mutant tau. In these Tau-P301L FBOs, tau fibrils were observed in the neuronal cell body and neurites with immunoelectron microscopy, in addition to the sarkosyl-insoluble and thioflavin S-positive phospho-tau aggregates. Collectively, this model can be used as a platform for investigating pathogenetic mechanisms and evaluation of target molecules for drug discovery for tauopathy.
Topics: Humans; Alzheimer Disease; Dependovirus; Induced Pluripotent Stem Cells; Organoids; Prosencephalon; tau Proteins; Tauopathies; Gene Transfer Techniques
PubMed: 36160042
DOI: 10.1016/j.crmeth.2022.100289 -
Proceedings of the National Academy of... Jul 2023The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural...
The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.
Topics: Cholinergic Agents; Acetylcholine; Prosencephalon; Cholinergic Neurons; gamma-Aminobutyric Acid; Logic
PubMed: 37399414
DOI: 10.1073/pnas.2218830120 -
Nature Communications Apr 2022In the developing mouse forebrain, temporally distinct waves of oligodendrocyte progenitor cells (OPCs) arise from different germinal zones and eventually populate...
In the developing mouse forebrain, temporally distinct waves of oligodendrocyte progenitor cells (OPCs) arise from different germinal zones and eventually populate either dorsal or ventral regions, where they present as transcriptionally and functionally equivalent cells. Despite that, developmental heterogeneity influences adult OPC responses upon demyelination. Here we show that accumulation of DNA damage due to ablation of citron-kinase or cisplatin treatment cell-autonomously disrupts OPC fate, resulting in cell death and senescence in the dorsal and ventral subsets, respectively. Such alternative fates are associated with distinct developmental origins of OPCs, and with a different activation of NRF2-mediated anti-oxidant responses. These data indicate that, upon injury, dorsal and ventral OPC subsets show functional and molecular diversity that can make them differentially vulnerable to pathological conditions associated with DNA damage.
Topics: Animals; DNA Damage; Mice; Oligodendrocyte Precursor Cells; Oligodendroglia; Prosencephalon
PubMed: 35484145
DOI: 10.1038/s41467-022-30010-6 -
Cell Apr 2024Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite...
Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis.
Topics: Animals; Prosencephalon; Mice; Rats; Blastocyst; Female; CRISPR-Cas Systems; Transcriptome; Organogenesis; Clustered Regularly Interspaced Short Palindromic Repeats; Male; Mice, Inbred C57BL
PubMed: 38670071
DOI: 10.1016/j.cell.2024.03.017 -
Frontiers in Neural Circuits 2021Social behaviors entail responses to social information and requires the perception and integration of social cues through a complex cognition process that involves... (Review)
Review
Social behaviors entail responses to social information and requires the perception and integration of social cues through a complex cognition process that involves attention, memory, motivation, and emotion. Neurobiological and molecular mechanisms underlying social behavior are highly conserved across species, and inter- and intra-specific variability observed in social behavior can be explained to large extent by differential activity of a conserved neural network. However, neural microcircuits and precise networks involved in social behavior remain mysterious. In this review, we summarize the microcircuits and input-output circuits on the molecular, cellular, and network levels of different social interactions, such as social exploration, social hierarchy, social memory, and social preference. This review provides a broad view of how multiple microcircuits and input-output circuits converge on the medial prefrontal cortex, hippocampus, and amygdala to regulate complex social behaviors, as well as a potential novel view for better control over pathological development.
Topics: Amygdala; Attention; Emotions; Hippocampus; Neural Pathways; Prefrontal Cortex; Social Behavior
PubMed: 34776877
DOI: 10.3389/fncir.2021.768294 -
Nature Neuroscience Nov 2023In addition to its motor functions, the cerebellum is involved in emotional regulation, anxiety and affect. We found that suppressing the firing of cerebellar Purkinje...
In addition to its motor functions, the cerebellum is involved in emotional regulation, anxiety and affect. We found that suppressing the firing of cerebellar Purkinje cells (PCs) rapidly excites forebrain areas that contribute to such functions (including the amygdala, basal forebrain and septum), but that the classic cerebellar outputs, the deep cerebellar nuclei, do not directly project there. We show that PCs directly inhibit parabrachial nuclei (PBN) neurons that project to numerous forebrain regions. Suppressing the PC-PBN pathway influences many regions in the forebrain and is aversive. Molecular profiling shows that PCs directly inhibit numerous types of PBN neurons that control diverse behaviors that are not involved in motor control. Therefore, the PC-PBN pathway allows the cerebellum to directly regulate activity in the forebrain, and may be an important substrate for cerebellar disorders arising from damage to the posterior vermis.
Topics: Purkinje Cells; Parabrachial Nucleus; Cerebellum; Prosencephalon; Neurons
PubMed: 37919612
DOI: 10.1038/s41593-023-01462-w -
Brain Structure & Function Mar 2023The primate forebrain is a complex structure. Thousands of connections have been identified between cortical areas, and between cortical and sub-cortical areas. Previous... (Review)
Review
The primate forebrain is a complex structure. Thousands of connections have been identified between cortical areas, and between cortical and sub-cortical areas. Previous work, however, has suggested that a number of principles can be used to reduce this complexity. Here, we integrate four principles that have been put forth previously, including a nested model of neocortical connectivity, gradients of connectivity between frontal cortical areas and the striatum and thalamus, shared patterns of sub-cortical connectivity between connected posterior and frontal cortical areas, and topographic organization of cortical-striatal-pallidal-thalamocortical circuits. We integrate these principles into a single model that accounts for a substantial amount of connectivity in the forebrain. We then suggest that studies in evolution and development can account for these four principles, by assuming that the ancestral vertebrate pallium was dominated by medial, hippocampal and ventral-lateral, pyriform areas, and at most a small dorsal pallium. The small dorsal pallium expanded massively in the lineage leading to primates. During this expansion, topological, adjacency relationships were maintained between pallial and sub-pallial areas. This maintained topology led to the connectivity gradients seen between cortex, striatum, pallidum, and thalamus.
Topics: Animals; Prosencephalon; Thalamus; Primates; Frontal Lobe; Vertebrates; Neural Pathways
PubMed: 36271258
DOI: 10.1007/s00429-022-02586-8