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Behavioural Brain Research Aug 2009A primary aim in the neuroscientific study of depression is to identify the brain areas involved in the pathogenesis of symptoms. In this review, we describe evidence... (Review)
Review
A primary aim in the neuroscientific study of depression is to identify the brain areas involved in the pathogenesis of symptoms. In this review, we describe evidence from studies employing various experimental approaches in humans (functional imaging, lesion method, and brain stimulation) that converge to implicate the ventromedial and dorsolateral sectors of prefrontal cortex as critical neural substrates for depression, albeit with distinct functional contributions. The putative roles of ventromedial and dorsolateral prefrontal cortex in depression are discussed in light of the results.
Topics: Brain Mapping; Depression; Depressive Disorder; Humans; Prefrontal Cortex; Transcranial Magnetic Stimulation
PubMed: 19428640
DOI: 10.1016/j.bbr.2009.03.004 -
The Journal of Neuroscience : the... May 2023Regional cellular heterogeneity is a fundamental feature of the human neocortex; however, details of this heterogeneity are still undefined. We used single-nucleus...
Regional cellular heterogeneity is a fundamental feature of the human neocortex; however, details of this heterogeneity are still undefined. We used single-nucleus RNA-sequencing to examine cell-specific transcriptional features in the dorsolateral PFC (DLPFC) and the subgenual anterior cingulate cortex (sgACC), regions implicated in major psychiatric disorders. Droplet-based nuclei-capture and library preparation were performed on replicate samples from 8 male donors without history of psychiatric or neurologic disorder. Unsupervised clustering identified major neural cell classes. Subsequent iterative clustering of neurons further revealed 20 excitatory and 22 inhibitory subclasses. Inhibitory cells were consistently more abundant in the sgACC and excitatory neuron subclusters exhibited considerable variability across brain regions. Excitatory cell subclasses also exhibited greater within-class transcriptional differences between the two regions. We used these molecular definitions to determine which cell classes might be enriched in loci carrying a genetic signal in genome-wide association studies or for differentially expressed genes in mental illness. We found that the heritable signals of psychiatric disorders were enriched in neurons and that, while the gene expression changes detected in bulk-RNA-sequencing studies were dominated by glial cells, some alterations could be identified in specific classes of excitatory and inhibitory neurons. Intriguingly, only two excitatory cell classes exhibited concomitant region-specific enrichment for both genome-wide association study loci and transcriptional dysregulation. In sum, by detailing the molecular and cellular diversity of the DLPFC and sgACC, we were able to generate hypotheses on regional and cell-specific dysfunctions that may contribute to the development of mental illness. Dysfunction of the subgenual anterior cingulate cortex has been implicated in mood disorders, particularly major depressive disorder, and the dorsolateral PFC, a subsection of the PFC involved in executive functioning, has been implicated in schizophrenia. Understanding the cellular composition of these regions is critical to elucidating the neurobiology underlying psychiatric and neurologic disorders. We studied cell type diversity of the subgenual anterior cingulate cortex and dorsolateral PFC of humans with no neuropsychiatric illness using a clustering analysis of single-nuclei RNA-sequencing data. Defining the transcriptomic profile of cellular subpopulations in these cortical regions is a first step to demystifying the cellular and molecular pathways involved in psychiatric disorders.
Topics: Humans; Male; Dorsolateral Prefrontal Cortex; Depressive Disorder, Major; Gyrus Cinguli; Prefrontal Cortex; Genome-Wide Association Study; Solitary Nucleus
PubMed: 37037607
DOI: 10.1523/JNEUROSCI.0830-22.2023 -
The Journal of Neuroscience : the... Nov 2020Several decades of research have established that different kinds of memories result from the activity of discrete neural networks. Studying how these networks process...
Several decades of research have established that different kinds of memories result from the activity of discrete neural networks. Studying how these networks process information in experiments that target specific types of mnemonic representations has provided deep insights into memory architecture and its neural underpinnings. However, in natural settings reality confronts organisms with problems that are not neatly compartmentalized. Thus, a critical problem in memory research that still needs to be addressed is how distinct types of memories are ultimately integrated. Here we demonstrate how two memory networks, the hippocampus and dorsolateral striatum, may accomplish such a goal. The hippocampus supports memory for facts and events, collectively known as declarative memory and often studied as spatial memory in rodents. The dorsolateral striatum provides the basis for habits that are assessed in stimulus-response types of tasks. Expanding previous findings, the current work revealed that in male Long-Evans rats, the hippocampus and dorsolateral striatum use time and space in distinct and largely complementary ways to integrate spatial and habitual representations. Specifically, the hippocampus supported both types of memories when they were formed in temporal juxtaposition, even if the learning took place in different environments. In contrast, the lateral striatum supported both types of memories if they were formed in the same environment, even at temporally distinct points. These results reveal for the first time that by using fundamental aspects of experience in specific ways, the hippocampus and dorsolateral striatum can transcend their attributed roles in information storage. The current paradigm in memory research postulates that different types of memories reflected in separate types of behavioral strategies result from activity in distinct neural circuits. However, recent data have shown that when rats concurrently acquired in the same environment of hippocampal-dependent spatial navigation and striatal-dependent approach of a visual cue, each of the two types of memories became dependent on both the hippocampus and dorsolateral striatum. The current work reveals that the hippocampus and dorsolateral striatum use distinct and complementary principles to integrate different types of memories in time and space: the hippocampus integrates memories formed in temporal proximity, while the lateral striatum integrates memories formed in the same space.
Topics: Animals; Corpus Striatum; Cues; Hippocampus; Male; Maze Learning; Memory; Psychomotor Performance; Rats; Rats, Long-Evans; Space Perception; Spatial Navigation; Time Perception
PubMed: 33051349
DOI: 10.1523/JNEUROSCI.1084-20.2020 -
ELife Nov 2021Theoretical accounts distinguish between motivational ('wanting') and hedonic ('liking') dimensions of rewards. Previous animal and human research linked wanting and... (Randomized Controlled Trial)
Randomized Controlled Trial
Theoretical accounts distinguish between motivational ('wanting') and hedonic ('liking') dimensions of rewards. Previous animal and human research linked wanting and liking to anatomically and neurochemically distinct brain mechanisms, but it remains unknown how the different brain regions and neurotransmitter systems interact in processing distinct reward dimensions. Here, we assessed how pharmacological manipulations of opioid and dopamine receptor activation modulate the neural processing of wanting and liking in humans in a randomized, placebo-controlled, double-blind clinical trial. Reducing opioid receptor activation with naltrexone selectively reduced wanting of rewards, which on a neural level was reflected by stronger coupling between dorsolateral prefrontal cortex and the striatum under naltrexone compared with placebo. In contrast, reducing dopaminergic neurotransmission with amisulpride revealed no robust effects on behavior or neural activity. Our findings thus provide insights into how opioid receptors mediate neural connectivity related to specifically motivational, not hedonic, aspects of rewards.
Topics: Adult; Amisulpride; Corpus Striatum; Dopamine Antagonists; Dorsolateral Prefrontal Cortex; Double-Blind Method; Female; Healthy Volunteers; Humans; Magnetic Resonance Imaging; Male; Motivation; Naltrexone; Narcotic Antagonists; Reward
PubMed: 34761749
DOI: 10.7554/eLife.71077 -
ELife Jun 2023Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a...
Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preBötzinger complex (preBötC) and rostral ventral respiratory group (rVRG). These medullary-projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBötC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preBötC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms-somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla-all of which could contribute to opioid-induced respiratory depression.
Topics: Analgesics, Opioid; Medulla Oblongata; Neurons; Pons; Respiration
PubMed: 37314062
DOI: 10.7554/eLife.81119 -
Proceedings of the National Academy of... May 2022Neurulation is the process in early vertebrate embryonic development during which the neural plate folds to form the neural tube. Spinal neural tube folding in the...
Neurulation is the process in early vertebrate embryonic development during which the neural plate folds to form the neural tube. Spinal neural tube folding in the posterior neuropore changes over time, first showing a median hinge point, then both the median hinge point and dorsolateral hinge points, followed by dorsolateral hinge points only. The biomechanical mechanism of hinge point formation in the mammalian neural tube is poorly understood. Here we employ a mechanical finite element model to study neural tube formation. The computational model mimics the mammalian neural tube using microscopy data from mouse and human embryos. While intrinsic curvature at the neural plate midline has been hypothesized to drive neural tube folding, intrinsic curvature was not sufficient for tube closure in our simulations. We achieved neural tube closure with an alternative model combining mesoderm expansion, nonneural ectoderm expansion, and neural plate adhesion to the notochord. Dorsolateral hinge points emerged in simulations with low mesoderm expansion and zippering. We propose that zippering provides the biomechanical force for dorsolateral hinge point formation in settings where the neural plate lateral sides extend above the mesoderm. Together, these results provide a perspective on the biomechanical and molecular mechanism of mammalian spinal neurulation.
Topics: Animals; Ectoderm; Humans; Mice; Neural Plate; Neural Tube; Neurulation; Notochord
PubMed: 35561223
DOI: 10.1073/pnas.2117075119 -
Frontiers in Neuroscience 2018In naturalistic multi-cue and multi-step learning tasks, where outcomes of behavior are delayed in time, discovering which choices are responsible for rewards can... (Review)
Review
In naturalistic multi-cue and multi-step learning tasks, where outcomes of behavior are delayed in time, discovering which choices are responsible for rewards can present a challenge, known as the . In this review, I summarize recent work that highlighted a critical role for the prefrontal cortex (PFC) in assigning credit where it is due in tasks where only a few of the multitude of cues or choices are relevant to the final outcome of behavior. Collectively, these investigations have provided compelling support for specialized roles of the orbitofrontal (OFC), anterior cingulate (ACC), and dorsolateral prefrontal (dlPFC) cortices in contingent learning. However, recent work has similarly revealed shared contributions and emphasized rich and heterogeneous response properties of neurons in these brain regions. Such functional overlap is not surprising given the complexity of reciprocal projections spanning the PFC. In the concluding section, I overview the evidence suggesting that the OFC, ACC and dlPFC communicate extensively, sharing the information about presented options, executed decisions and received rewards, which enables them to assign credit for outcomes to choices on which they are contingent. This account suggests that lesion or inactivation/inhibition experiments targeting a localized PFC subregion will be insufficient to gain a fine-grained understanding of credit assignment during learning and instead poses refined questions for future research, shifting the focus from focal manipulations to experimental techniques targeting cortico-cortical projections.
PubMed: 29636659
DOI: 10.3389/fnins.2018.00182 -
Biomedical Papers of the Medical... Mar 2022In this study we evaluated the impact of location of deep brain stimulation electrode active contact in different parts of the subthalamic nucleus on improvement of...
BACKGROUND
In this study we evaluated the impact of location of deep brain stimulation electrode active contact in different parts of the subthalamic nucleus on improvement of non-motor symptoms in patients with Parkinson's disease.
METHODS
The subthalamic nucleus was divided into two (dorsolateral/ventromedial) and three (dorsolateral, medial, ventromedial) parts. 37 deep brain stimulation electrodes were divided according to their active contact location. Correlation between change in non-motor symptoms before and one and four months after deep brain stimulation electrode implantation and the location of active contact was made.
RESULTS
In dividing the subthalamic nucleus into three parts, no electrode active contact was placed ventromedially, 28 active contacts were located in the medial part and 9 contacts were placed dorsolaterally. After one and four months, no significant difference was found between medial and dorsolateral positions. In the division of the subthalamic nucleus into two parts, 13 contacts were located in the ventromedial part and 24 contacts were placed in the dorsolateral part. After one month, significantly greater improvement in the Non-motor Symptoms Scale for Parkinson's disease (P=0.045) was found on dorsolateral left-sided stimulation, but no significant differences between the ventromedial and dorsolateral positions were found on the right side.
CONCLUSION
This study demonstrated the relationship between improvement of non-motor symptoms and the side (hemisphere, left/right) of the deep brain stimulation electrode active contact, rather than its precise location within specific parts of the subthalamic nucleus in patients treated for advanced Parkinson's disease.
Topics: Deep Brain Stimulation; Electrodes; Humans; Parkinson Disease; Subthalamic Nucleus; Treatment Outcome
PubMed: 33883752
DOI: 10.5507/bp.2020.034