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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 -
Nature Communications Jul 2023Episodic memory-based decision-making requires top-down medial prefrontal cortex and hippocampal interactions. This integrated prefrontal-hippocampal memory state is...
Episodic memory-based decision-making requires top-down medial prefrontal cortex and hippocampal interactions. This integrated prefrontal-hippocampal memory state is thought to be organized by synchronized network oscillations and mediated by connectivity with the thalamic nucleus reuniens (RE). Whether and how the RE synchronizes prefrontal-hippocampal networks in memory, however, remains unknown. Here, we recorded local field potentials from the prefrontal-RE-hippocampal network while rats engaged in a nonspatial sequence memory task, thereby isolating memory-related activity from running-related oscillations. We found that synchronous prefrontal-hippocampal beta bursts (15-30 Hz) dominated during memory trials, whereas synchronous theta activity (6-12 Hz) dominated during non-memory-related running. Moreover, RE beta activity appeared first, followed by prefrontal and hippocampal synchronized beta, suggesting that prefrontal-hippocampal beta could be driven by the RE. To test whether the RE is capable of driving prefrontal-hippocampal beta synchrony, we used an optogenetic approach (retroAAV-ChR2). RE activation induced prefrontal-hippocampal beta coherence and reduced theta coherence, matching the observed memory-driven network state in the sequence task. These findings are the first to demonstrate that the RE contributes to memory by driving transient synchronized beta in the prefrontal-hippocampal system, thereby facilitating interactions that underlie memory-based decision-making.
Topics: Rats; Animals; Midline Thalamic Nuclei; Prefrontal Cortex; Hippocampus; Thalamic Nuclei; Neural Pathways
PubMed: 37468487
DOI: 10.1038/s41467-023-40044-z -
Current Opinion in Neurobiology Apr 2024The entorhinal cortex and hippocampus form a recurrent network that informs many cognitive processes, including memory, planning, navigation, and imagination. Neural... (Review)
Review
The entorhinal cortex and hippocampus form a recurrent network that informs many cognitive processes, including memory, planning, navigation, and imagination. Neural recordings from these regions reveal spatially organized population codes corresponding to external environments and abstract spaces. Aligning the former cognitive functionalities with the latter neural phenomena is a central challenge in understanding the entorhinal-hippocampal circuit (EHC). Disparate experiments demonstrate a surprising level of complexity and apparent disorder in the intricate spatiotemporal dynamics of sequential non-local hippocampal reactivations, which occur particularly, though not exclusively, during immobile pauses and rest. We review these phenomena with a particular focus on their apparent lack of physical simulative realism. These observations are then integrated within a theoretical framework and proposed neural circuit mechanisms that normatively characterize this neural complexity by conceiving different regimes of hippocampal microdynamics as neuromarkers of diverse cognitive computations.
Topics: Space Perception; Entorhinal Cortex; Hippocampus; Cognition; Models, Neurological
PubMed: 38428170
DOI: 10.1016/j.conb.2024.102855 -
Annual Review of Neuroscience Jul 2023Flexible behavior requires the creation, updating, and expression of memories to depend on context. While the neural underpinnings of each of these processes have been... (Review)
Review
Flexible behavior requires the creation, updating, and expression of memories to depend on context. While the neural underpinnings of each of these processes have been intensively studied, recent advances in computational modeling revealed a key challenge in context-dependent learning that had been largely ignored previously: Under naturalistic conditions, context is typically uncertain, necessitating contextual inference. We review a theoretical approach to formalizing context-dependent learning in the face of contextual uncertainty and the core computations it requires. We show how this approach begins to organize a large body of disparate experimental observations, from multiple levels of brain organization (including circuits, systems, and behavior) and multiple brain regions (most prominently the prefrontal cortex, the hippocampus, and motor cortices), into a coherent framework. We argue that contextual inference may also be key to understanding continual learning in the brain. This theory-driven perspective places contextual inference as a core component of learning.
Topics: Learning; Brain; Hippocampus; Prefrontal Cortex; Computer Simulation
PubMed: 36972611
DOI: 10.1146/annurev-neuro-092322-100402 -
Cell Reports Oct 2023The paraventricular nucleus of the thalamus (PVT) projects axons to multiple areas, mediates a wide range of behaviors, and exhibits regional heterogeneity in both...
The paraventricular nucleus of the thalamus (PVT) projects axons to multiple areas, mediates a wide range of behaviors, and exhibits regional heterogeneity in both functions and axonal projections. Still, questions regarding the cell types present in the PVT and the extent of their differences remain inadequately addressed. We applied single-cell RNA sequencing to depict the transcriptomic characteristics of mouse PVT neurons. We found that one of the most significant variances in the PVT transcriptome corresponded to the anterior-posterior axis. While the single-cell transcriptome classified PVT neurons into five types, our transcriptomic and histological analyses showed continuity among the cell types. We discovered that anterior and posterior subpopulations had nearly non-overlapping projection patterns, while another population showed intermediate patterns. In addition, these subpopulations responded differently to appetite-related neuropeptides, with their activation showing opposing effects on food consumption. Our studies unveiled the contrasts and the continuity of PVT neurons that underpin their function.
Topics: Animals; Mice; Midline Thalamic Nuclei; Paraventricular Hypothalamic Nucleus; Thalamus; Transcriptome
PubMed: 37862168
DOI: 10.1016/j.celrep.2023.113309 -
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 -
Neuron Apr 2024The hippocampus has long been at the center of memory research, and rightfully so. However, with emerging technological capabilities, we can increasingly appreciate... (Review)
Review
The hippocampus has long been at the center of memory research, and rightfully so. However, with emerging technological capabilities, we can increasingly appreciate memory as a more dynamic and brain-wide process. In this perspective, our goal is to begin developing models to understand the gradual evolution, reorganization, and stabilization of memories across the brain after their initial formation in the hippocampus. By synthesizing studies across the rodent and human literature, we suggest that as memory representations initially form in hippocampus, parallel traces emerge in frontal cortex that cue memory recall, and as they mature, with sustained support initially from limbic then diencephalic then cortical circuits, they become progressively independent of hippocampus and dependent on a mature cortical representation. A key feature of this model is that, as time progresses, memory representations are passed on to distinct circuits with progressively longer time constants, providing the opportunity to filter, forget, update, or reorganize memories in the process of committing to long-term storage.
Topics: Animals; Humans; Prefrontal Cortex; Hippocampus; Memory; Thalamus; Rodentia
PubMed: 38272026
DOI: 10.1016/j.neuron.2023.12.021 -
Annals of Clinical and Translational... Dec 2023Further understanding of the function and regulatory mechanism of cholinergic neural circuits and related neurodegenerative diseases. (Review)
Review
OBJECTIVE
Further understanding of the function and regulatory mechanism of cholinergic neural circuits and related neurodegenerative diseases.
METHODS
This review summarized the research progress of the central cholinergic nervous system, especially for the cholinergic circuit of the medial septal nucleus-hippocampus, vertical branch of diagonal band-hippocampus, basal nucleus of Meynert-cerebral cortex cholinergic loop, amygdala, pedunculopontine nucleus, and striatum-related cholinergic loops.
RESULTS
The extensive and complex fiber projection of cholinergic neurons form the cholinergic neural circuits, which regulate several nuclei in the brain through neurotransmission and participate in learning and memory, attention, emotion, movement, etc. The loss of cholinergic neurotransmitters, the reduction, loss, and degeneration of cholinergic neurons or abnormal theta oscillations and cholinergic neural circuits can induce cognitive disorders such as AD, PD, PDD, and DLB.
INTERPRETATION
The projection and function of cholinergic fibers in some nuclei and the precise regulatory mechanisms of cholinergic neural circuits in the brain remain unclear. Further investigation of cholinergic fiber projections in various brain regions and the underlying mechanisms of the neural circuits are expected to open up new avenues for the prevention and treatment of senile neurodegenerative diseases.
Topics: Humans; Central Nervous System; Hippocampus; Cerebral Cortex; Neurodegenerative Diseases; Cholinergic Agents
PubMed: 37846148
DOI: 10.1002/acn3.51920 -
Cell Oct 2023Human reasoning depends on reusing pieces of information by putting them together in new ways. However, very little is known about how compositional computation is...
Human reasoning depends on reusing pieces of information by putting them together in new ways. However, very little is known about how compositional computation is implemented in the brain. Here, we ask participants to solve a series of problems that each require constructing a whole from a set of elements. With fMRI, we find that representations of novel constructed objects in the frontal cortex and hippocampus are relational and compositional. With MEG, we find that replay assembles elements into compounds, with each replay sequence constituting a hypothesis about a possible configuration of elements. The content of sequences evolves as participants solve each puzzle, progressing from predictable to uncertain elements and gradually converging on the correct configuration. Together, these results suggest a computational bridge between apparently distinct functions of hippocampal-prefrontal circuitry and a role for generative replay in compositional inference and hypothesis testing.
Topics: Humans; Brain; Frontal Lobe; Hippocampus; Magnetic Resonance Imaging; Neural Pathways; Prefrontal Cortex
PubMed: 37804832
DOI: 10.1016/j.cell.2023.09.004 -
Neuron Oct 2023Basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for appropriate emotional responding and...
Basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for appropriate emotional responding and decision making. While it is appreciated that single BLA neurons branch and project to multiple areas in frontal cortex, the organization and frequency of this branching has yet to be fully characterized. Here, we determined the projection patterns of more than 3,000 macaque BLA neurons. We found that one-third of BLA neurons had two or more distinct projection targets in frontal cortex and subcortical structures. The patterns of single BLA neuron projections to multiple areas were organized into repeating motifs that targeted distinct sets of areas in medial and ventral frontal cortex, indicative of separable BLA networks. Our findings begin to reveal the rich structure of single-neuron connections in the non-human primate brain, providing a neuroanatomical basis for the role of BLA in coordinating brain-wide responses to valent stimuli.
Topics: Animals; Basolateral Nuclear Complex; Macaca; Neural Pathways; Frontal Lobe; Neurons; Prefrontal Cortex
PubMed: 37857091
DOI: 10.1016/j.neuron.2023.09.024