@article {2188, title = {Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases.}, journal = {Science}, volume = {375}, year = {2022}, month = {2022 02 04}, pages = {522-528}, abstract = {

To determine the impact of genetic variants on the brain, we used genetically informed brain atlases in genome-wide association studies of regional cortical surface area and thickness in 39,898 adults and 9136 children. We uncovered 440 genome-wide significant loci in the discovery cohort and 800 from a post hoc combined meta-analysis. Loci in adulthood were largely captured in childhood, showing signatures of negative selection, and were linked to early neurodevelopment and pathways associated with neuropsychiatric risk. Opposing gradations of decreased surface area and increased thickness were associated with common inversion polymorphisms. Inferior frontal regions, encompassing Broca{\textquoteright}s area, which is important for speech, were enriched for human-specific genomic elements. Thus, a mixed genetic landscape of conserved and human-specific features is concordant with brain hierarchy and morphogenetic gradients.

}, keywords = {Adult, Aged, Aged, 80 and over, Cerebral Cortex, Child, Chromatin, Cohort Studies, Female, Gene Ontology, Genetic Association Studies, Genetic Loci, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Mental Disorders, Middle Aged, Molecular Sequence Annotation, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid}, issn = {1095-9203}, doi = {10.1126/science.abe8457}, author = {Makowski, Carolina and van der Meer, Dennis and Dong, Weixiu and Wang, Hao and Wu, Yan and Zou, Jingjing and Liu, Cin and Rosenthal, Sara B and Hagler, Donald J and Fan, Chun Chieh and Kremen, William S and Andreassen, Ole A and Jernigan, Terry L and Dale, Anders M and Zhang, Kun and Visscher, Peter M and Yang, Jian and Chen, Chi-Hua} } @article {1789, title = {Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength.}, journal = {Elife}, volume = {10}, year = {2021}, month = {2021 Jan 21}, abstract = {

The conserved MAP3K Dual-Leucine-Zipper Kinase (DLK) and Leucine-Zipper-bearing Kinase (LZK) can activate JNK via MKK4 or MKK7. These two MAP3Ks share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of , strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

}, issn = {2050-084X}, doi = {10.7554/eLife.63509}, author = {Li, Yunbo and Ritchie, Erin M and Steinke, Christopher L and Qi, Cai and Chen, Lizhen and Zheng, Binhai and Jin, Yishi} } @article {1648, title = {Fast near-whole-brain imaging in adult Drosophila during responses to stimuli and behavior.}, journal = {PLoS Biol}, volume = {17}, year = {2019}, month = {2019 Feb}, pages = {e2006732}, abstract = {

Whole-brain recordings give us a global perspective of the brain in action. In this study, we describe a method using light field microscopy to record near-whole brain calcium and voltage activity at high speed in behaving adult flies. We first obtained global activity maps for various stimuli and behaviors. Notably, we found that brain activity increased on a global scale when the fly walked but not when it groomed. This global increase with walking was particularly strong in dopamine neurons. Second, we extracted maps of spatially distinct sources of activity as well as their time series using principal component analysis and independent component analysis. The characteristic shapes in the maps matched the anatomy of subneuropil regions and, in some cases, a specific neuron type. Brain structures that responded to light and odor were consistent with previous reports, confirming the new technique{\textquoteright}s validity. We also observed previously uncharacterized behavior-related activity as well as patterns of spontaneous voltage activity.

}, issn = {1545-7885}, doi = {10.1371/journal.pbio.2006732}, author = {Aimon, Sophie and Katsuki, Takeo and Jia, Tongqiu and Grosenick, Logan and Broxton, Michael and Deisseroth, Karl and Sejnowski, Terrence J and Greenspan, Ralph J} } @article {1674, title = {Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study.}, journal = {Int J Geriatr Psychiatry}, volume = {32}, year = {2017}, month = {2017 Mar}, pages = {341-349}, abstract = {

OBJECTIVE: Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called {\textquoteright}inflammaging.{\textquoteright} Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults.

METHODS: Twenty-four older adults (mean age = 78) underwent a functional magnetic resonance imaging (fMRI) resting state functional connectivity scan, and a subset (n = 14) completed the n-Back working memory task in the scanner. All participants completed a blood draw, and inflammation was measured with interleukin 6 (IL-6) and C-Reactive Protein (CRP).

RESULTS: Surprisingly, age was unrelated to measures of inflammation (IL-6, CRP) or brain function (default mode network (DMN) connectivity; working memory performance; blood oxygenation level dependent (BOLD) activation with higher working memory load). However, lower functional connectivity between the left parietal seed and all other DMN regions was associated with higher levels of IL-6 and CRP. Additionally, greater plasma concentration of IL-6 was associated with lower BOLD activation in the left middle frontal gyrus in response to increased working memory load.

CONCLUSIONS: These preliminary findings support the importance of IL-6 and CRP in brain function among older adults. Frontal and parietal regions may be particularly sensitive to the effects of inflammation. Additionally, these findings provide preliminary evidence of inflammatory contributions to level of neural activity, even after accounting for vascular risk factors.

}, keywords = {Aged, Brain Mapping, C-Reactive Protein, Cognition, Cognitive Dysfunction, Female, Frontal Lobe, Humans, Inflammation, Interleukin-6, Magnetic Resonance Imaging, Male, Memory, Short-Term, Parietal Lobe, Rest}, issn = {1099-1166}, doi = {10.1002/gps.4482}, author = {Dev, Sheena I and Moore, Raeanne C and Soontornniyomkij, Benchawanna and Achim, Cristian L and Jeste, Dilip V and Eyler, Lisa T} } @article {128, title = {Generation of functional human serotonergic neurons from fibroblasts.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 Jan}, pages = {49-61}, abstract = {

The brain{\textquoteright}s serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.161}, author = {Vadodaria, K C and Mertens, J and Paquola, A and Bardy, C and Li, X and Jappelli, R and Fung, L and Marchetto, M C and Hamm, M and Gorris, M and Koch, P and Gage, F H} } @article {125, title = {Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness.}, journal = {Neurobiol Learn Mem}, volume = {129}, year = {2016}, month = {2016 Mar}, pages = {60-8}, abstract = {

Hippocampal adult neurogenesis is thought to subserve pattern separation, the process by which similar patterns of neuronal inputs are transformed into distinct neuronal representations, permitting the discrimination of highly similar stimuli in hippocampus-dependent tasks. However, the mechanism by which immature adult-born dentate granule neurons cells (abDGCs) perform this function remains unknown. Two theories of abDGC function, one by which abDGCs modulate and sparsify activity in the dentate gyrus and one by which abDGCs act as autonomous coding units, are generally suggested to be mutually exclusive. This review suggests that these two mechanisms work in tandem to dynamically regulate memory resolution while avoiding memory interference and maintaining memory robustness.

}, issn = {1095-9564}, doi = {10.1016/j.nlm.2015.10.013}, author = {Johnston, Stephen T and Shtrahman, Matthew and Parylak, Sarah and Gon{\c c}alves, J Tiago and Gage, Fred H} } @article {124, title = {Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders.}, journal = {Stem Cell Reports}, volume = {5}, year = {2015}, month = {2015 Dec 8}, pages = {933-45}, abstract = {

As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.

}, issn = {2213-6711}, doi = {10.1016/j.stemcr.2015.10.011}, author = {Brennand, Kristen J and Marchetto, M Carol and Benvenisty, Nissim and Br{\"u}stle, Oliver and Ebert, Allison and Izpisua Belmonte, Juan Carlos and Kaykas, Ajamete and Lancaster, Madeline A and Livesey, Frederick J and McConnell, Michael J and McKay, Ronald D and Morrow, Eric M and Muotri, Alysson R and Panchision, David M and Rubin, Lee L and Sawa, Akira and Soldner, Frank and Song, Hongjun and Studer, Lorenz and Temple, Sally and Vaccarino, Flora M and Wu, Jun and Vanderhaeghen, Pierre and Gage, Fred H and Jaenisch, Rudolf} } @article {1673, title = {Distinct neural correlates of emotional and cognitive empathy in older adults.}, journal = {Psychiatry Res}, volume = {232}, year = {2015}, month = {2015 Apr 30}, pages = {42-50}, abstract = {

Empathy is thought to be a mechanism underlying prosocial behavior across the lifespan, yet little is known about how levels of empathy relate to individual differences in brain functioning among older adults. In this exploratory study, we examined the neural correlates of affective and cognitive empathy in older adults. Thirty older adults (M=79 years) underwent fMRI scanning and neuropsychological testing and completed a test of affective and cognitive empathy. Brain response during processing of cognitive and emotional stimuli was measured by fMRI in a priori and task-related regions and was correlated with levels of empathy. Older adults with higher levels of affective empathy showed more deactivation in the amygdala and insula during a working memory task, whereas those with higher cognitive empathy showed greater insula activation during a response inhibition task. Our preliminary findings suggest that brain systems linked to emotional and social processing respond differently among older adults with more or less affective and cognitive empathy. That these relationships can be seen both during affective and non-emotional tasks of "cold" cognitive abilities suggests that empathy may impact social behavior through both emotional and cognitive mechanisms.

}, keywords = {Affect, Aged, Aged, 80 and over, Aging, Brain, Brain Mapping, Cognition, Emotions, Empathy, Female, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Social Behavior, Social Perception}, issn = {1872-7123}, doi = {10.1016/j.pscychresns.2014.10.016}, author = {Moore, Raeanne C and Dev, Sheena I and Jeste, Dilip V and Dziobek, Isabel and Eyler, Lisa T} } @article {199, title = {From suffering to caring: a model of differences among older adults in levels of compassion.}, journal = {Int J Geriatr Psychiatry}, volume = {30}, year = {2015}, month = {2015 Feb}, pages = {185-91}, abstract = {

OBJECTIVE: Compassion is an important contributor to pro-social behavior and maintenance of interpersonal relationships, yet little is known about what factors influence compassion in late life. The aim of this study was to test theories about how past and current stressors and emotional functioning, resilience, and demographic indicators of life experiences are related to compassion among older adults.

METHODS: One thousand and six older adults (50-99 years) completed a comprehensive survey including self-report measures of compassion, resilience, past and present stress, and emotional functioning (i.e., stressful life events, perceived stress, and current and prior depression and anxiety), and demographic information. The sample was randomly split, and exploratory and confirmatory regression analyses were conducted testing hypothesized relationships with compassion.

RESULTS: Exploratory stepwise regression analysis (n = 650) indicated that participants who reported higher levels of compassion were more likely to be female, not currently in a married/married-like relationship, reported higher resilience levels, and had experienced more significant life events. Age, income level, past and current mental distress, and interactions between resilience and other predictors were not significantly related to compassion. The associations between greater self-reported compassion and being female, having greater resilience, and having experienced more significant life events were supported by a confirmatory stepwise regression analysis (n = 356).

CONCLUSIONS: Older women report more compassion than older men. Resilience and significant life events, independently, also appear to facilitate a desire to help others, while current stress and past and present emotional functioning are less relevant. Specificity of findings to older adults is not yet known.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Empathy, Female, Humans, Life Change Events, Male, Marital Status, Middle Aged, Regression Analysis, Resilience, Psychological, Sex Factors, Socioeconomic Factors}, issn = {1099-1166}, doi = {10.1002/gps.4123}, author = {Moore, Raeanne C and Martin, A{\textquoteright}verria Sirkin and Kaup, Allison R and Thompson, Wesley K and Peters, Matthew E and Jeste, Dilip V and Golshan, Shahrokh and Eyler, Lisa T} } @article {122, title = {Transcriptional changes in sensory ganglia associated with primary afferent axon collateral sprouting in spared dermatome model.}, journal = {Genom Data}, volume = {6}, year = {2015}, month = {2015 Dec}, pages = {249-52}, abstract = {

Primary afferent collateral sprouting is a process whereby non-injured primary afferent neurons respond to some stimulus and extend new branches from existing axons. Neurons of both the central and peripheral nervous systems undergo this process, which contributes to both adaptive and maladaptive plasticity (e.g., [1], [2], [3], [4], [5], [6], [7], [8], [9]). In the model used here (the "spared dermatome" model), the intact sensory neurons respond to the denervation of adjacent areas of skin by sprouting new axon branches into that adjacent denervated territory. Investigations of gene expression changes associated with collateral sprouting can provide a better understanding of the molecular mechanisms controlling this process. Consequently, it can be used to develop treatments to promote functional recovery for spinal cord injury and other similar conditions. This report includes raw gene expression data files from microarray experiments in order to study the gene regulation in spared sensory ganglia in the initiation (7\ days) and maintenance (14\ days) phases of the spared dermatome model relative to intact ("na{\"\i}ve") sensory ganglia. Data has been deposited into GEO (GSE72551).

}, issn = {2213-5960}, doi = {10.1016/j.gdata.2015.10.005}, author = {Harrison, Benjamin J and Venkat, Gayathri and Hutson, Thomas and Rau, Kristofer K and Bunge, Mary Bartlett and Mendell, Lorne M and Gage, Fred H and Johnson, Richard D and Hill, Caitlin and Rouchka, Eric C and Moon, Lawrence and Petruska, Jeffrey C} } @article {213, title = {Sparse and distributed coding of episodic memory in neurons of the human hippocampus.}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, year = {2014}, month = {2014 Jul 1}, pages = {9621-6}, abstract = {

Neurocomputational models hold that sparse distributed coding is the most efficient way for hippocampal neurons to encode episodic memories rapidly. We investigated the representation of episodic memory in hippocampal neurons of nine epilepsy patients undergoing intracranial monitoring as they discriminated between recently studied words (targets) and new words (foils) on a recognition test. On average, single units and multiunits exhibited higher spike counts in response to targets relative to foils, and the size of this effect correlated with behavioral performance. Further analyses of the spike-count distributions revealed that (i) a small percentage of recorded neurons responded to any one target and (ii) a small percentage of targets elicited a strong response in any one neuron. These findings are consistent with the idea that in the human hippocampus episodic memory is supported by a sparse distributed neural code.

}, keywords = {Epilepsy, Hippocampus, Humans, Memory, Episodic, Models, Neurological, Neurophysiological Monitoring, Neuropsychological Tests}, issn = {1091-6490}, doi = {10.1073/pnas.1408365111}, author = {Wixted, John T and Squire, Larry R and Jang, Yoonhee and Papesh, Megan H and Goldinger, Stephen D and Kuhn, Joel R and Smith, Kris A and Treiman, David M and Steinmetz, Peter N} } @article {180, title = {Speech-specific tuning of neurons in human superior temporal gyrus.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Oct}, pages = {2679-93}, abstract = {

How the brain extracts words from auditory signals is an unanswered question. We recorded approximately 150 single and multi-units from the left anterior superior temporal gyrus of a patient during multiple auditory experiments. Against low background activity, 45\% of units robustly fired to particular spoken words with little or no response to pure tones, noise-vocoded speech, or environmental sounds. Many units were tuned to complex but specific sets of phonemes, which were influenced by local context but invariant to speaker, and suppressed during self-produced speech. The firing of several units to specific visual letters was correlated with their response to the corresponding auditory phonemes, providing the first direct neural evidence for phonological recoding during reading. Maximal decoding of individual phonemes and words identities was attained using firing rates from approximately 5 neurons within 200 ms after word onset. Thus, neurons in human superior temporal gyrus use sparse spatially organized population encoding of complex acoustic-phonetic features to help recognize auditory and visual words.

}, keywords = {Acoustic Stimulation, Adult, Humans, Male, Neurons, Phonetics, Speech Perception, Temporal Lobe}, issn = {1460-2199}, doi = {10.1093/cercor/bht127}, author = {Chan, Alexander M and Dykstra, Andrew R and Jayaram, Vinay and Leonard, Matthew K and Travis, Katherine E and Gygi, Brian and Baker, Janet M and Eskandar, Emad and Hochberg, Leigh R and Halgren, Eric and Cash, Sydney S} } @article {139, title = {Neurotransmitter switching in the adult brain regulates behavior.}, journal = {Science}, volume = {340}, year = {2013}, month = {2013 Apr 26}, pages = {449-53}, abstract = {

Neurotransmitters have been thought to be fixed throughout life, but whether sensory stimuli alter behaviorally relevant transmitter expression in the mature brain is unknown. We found that populations of interneurons in the adult rat hypothalamus switched between dopamine and somatostatin expression in response to exposure to short- and long-day photoperiods. Changes in postsynaptic dopamine receptor expression matched changes in presynaptic dopamine, whereas somatostatin receptor expression remained constant. Pharmacological blockade or ablation of these dopaminergic neurons led to anxious and depressed behavior, phenocopying performance after exposure to the long-day photoperiod. Induction of newly dopaminergic neurons through exposure to the short-day photoperiod rescued the behavioral consequences of lesions. Natural stimulation of other sensory modalities may cause changes in transmitter expression that regulate different behaviors.

}, keywords = {Animals, Behavior, Animal, Brain, Cell Count, Dopamine, Dopaminergic Neurons, Hypothalamus, Male, Maze Learning, Photoperiod, Rats, Rats, Long-Evans, Receptors, Dopamine, Receptors, Somatostatin, Seasons, Somatostatin, Stress, Psychological, Synaptic Transmission}, issn = {1095-9203}, doi = {10.1126/science.1234152}, author = {Dulcis, Davide and Jamshidi, Pouya and Leutgeb, Stefan and Spitzer, Nicholas C} } @article {160, title = {A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.}, journal = {PLoS Comput Biol}, volume = {5}, year = {2009}, month = {2009 Mar}, pages = {e1000334}, abstract = {

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

}, keywords = {Animals, Brain, Databases, Factual, Humans, Macaca, Mice, Models, Neurological, Nerve Net, Neuroanatomy, Research Design}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000334}, author = {Bohland, Jason W and Wu, Caizhi and Barbas, Helen and Bokil, Hemant and Bota, Mihail and Breiter, Hans C and Cline, Hollis T and Doyle, John C and Freed, Peter J and Greenspan, Ralph J and Haber, Suzanne N and Hawrylycz, Michael and Herrera, Daniel G and Hilgetag, Claus C and Huang, Z Josh and Jones, Allan and Jones, Edward G and Karten, Harvey J and Kleinfeld, David and K{\"o}tter, Rolf and Lester, Henry A and Lin, John M and Mensh, Brett D and Mikula, Shawn and Panksepp, Jaak and Price, Joseph L and Safdieh, Joseph and Saper, Clifford B and Schiff, Nicholas D and Schmahmann, Jeremy D and Stillman, Bruce W and Svoboda, Karel and Swanson, Larry W and Toga, Arthur W and Van Essen, David C and Watson, James D and Mitra, Partha P} }