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1.
Sci Data ; 11(1): 616, 2024 Jun 12.
Article En | MEDLINE | ID: mdl-38866804

The development and aging of the brain constitute a lifelong dynamic process, marked by structural and functional changes that entail highly coordinated cellular differentiation and epigenetic regulatory mechanisms. Chromatin accessibility serves as the foundational basis for genetic activity. However, the holistic and dynamic chromatin landscape that spans various brain regions throughout development and ageing remains predominantly unexplored. In this study, we employed single-nucleus ATAC-seq to generate comprehensive chromatin accessibility maps, incorporating data from 69,178 cells obtained from four distinct brain regions - namely, the olfactory bulb (OB), cerebellum (CB), prefrontal cortex (PFC), and hippocampus (HP) - across key developmental time points at 7 P, 3 M, 12 M, and 18 M. We delineated the distribution of cell types across different age stages and brain regions, providing insight into chromatin accessible regions and key transcription factors specific to different cell types. Our data contribute to understanding the epigenetic basis of the formation of different brain regions, providing a dynamic landscape and comprehensive resource for revealing gene regulatory programs during brain development and aging.


Aging , Brain , Chromatin , Animals , Chromatin/metabolism , Mice , Aging/genetics , Brain/growth & development , Brain/metabolism , Epigenesis, Genetic , Hippocampus/metabolism , Hippocampus/growth & development , Prefrontal Cortex/metabolism , Prefrontal Cortex/growth & development
2.
ACS Chem Neurosci ; 15(8): 1635-1642, 2024 04 17.
Article En | MEDLINE | ID: mdl-38557009

CHD8 is a high penetrance, high confidence risk gene for autism spectrum disorder (ASD), a neurodevelopmental disorder that is substantially more prevalent among males than among females. Recent studies have demonstrated variable sex differences in the behaviors and synaptic phenotypes of mice carrying different heterozygous ASD-associated mutations in Chd8. We examined functional and structural cellular phenotypes linked to synaptic transmission in deep layer pyramidal neurons of the prefrontal cortex in male and female mice carrying a heterozygous, loss-of-function Chd8 mutation in the C57BL/6J strain across development from postnatal day 2 to adulthood. Notably, excitatory neurotransmission was decreased only in Chd8+/- males with no differences in Chd8+/- females, and the majority of alterations in inhibitory transmission were found in males. Similarly, analysis of cellular morphology showed male-specific effects of reduced Chd8 expression. Both functional and structural phenotypes were most prominent at postnatal days 14-20, a stage approximately corresponding to childhood. Our findings suggest that the effects of Chd8 mutation are predominantly seen in males and are maximal during childhood.


Prefrontal Cortex , Animals , Female , Humans , Male , Mice , Autism Spectrum Disorder/genetics , Haploinsufficiency , Mice, Inbred C57BL , Phenotype , Prefrontal Cortex/growth & development
3.
Psychol Med ; 53(3): 759-770, 2023 02.
Article En | MEDLINE | ID: mdl-34105450

BACKGROUND: Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. METHODS: MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. RESULTS: VP children who met criteria for an anxiety disorder at 13 years (n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala (p = 0.0009) and left hippocampus (p = 0.029) compared with VP children without anxiety (n = 108), with trends in the right hippocampus (p = 0.062) and left medial orbitofrontal cortex (p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV (ß = -0.461, p = 0.020), TBV (ß = -0.503, p = 0.021), left (ß = -0.518, p = 0.020) and right hippocampi (ß = -0.469, p = 0.020) and left medial orbitofrontal cortex (ß = -0.761, p = 0.020) and did not persist after adjusting for TBV and social risk. CONCLUSIONS: Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.


Anxiety Disorders , Infant, Extremely Premature , Limbic Lobe , Prefrontal Cortex , Adolescent , Child , Female , Humans , Infant, Newborn , Male , Anxiety Disorders/diagnosis , Anxiety Disorders/epidemiology , Infant, Extremely Premature/growth & development , Interview, Psychological , Limbic Lobe/diagnostic imaging , Limbic Lobe/growth & development , Magnetic Resonance Imaging , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/growth & development , Prospective Studies , Longitudinal Studies
4.
Sci Rep ; 12(1): 21015, 2022 12 05.
Article En | MEDLINE | ID: mdl-36470912

Important functions of the prefrontal cortex (PFC) are established during early life, when neurons exhibit enhanced synaptic plasticity and synaptogenesis. This developmental stage drives the organization of cortical connectivity, responsible for establishing behavioral patterns. Serotonin (5-HT) emerges among the most significant factors that modulate brain activity during postnatal development. In the PFC, activated 5-HT receptors modify neuronal excitability and interact with intracellular signaling involved in synaptic modifications, thus suggesting that 5-HT might participate in early postnatal plasticity. To test this hypothesis, we employed intracellular electrophysiological recordings of PFC layer 5 neurons to study the modulatory effects of 5-HT on plasticity induced by theta-burst stimulation (TBS) in two postnatal periods of rats. Our results indicate that 5-HT is essential for TBS to result in synaptic changes during the third postnatal week, but not later. TBS coupled with 5-HT2A or 5-HT1A and 5-HT7 receptors stimulation leads to long-term depression (LTD). On the other hand, TBS and synergic activation of 5-HT1A, 5-HT2A, and 5-HT7 receptors lead to long-term potentiation (LTP). Finally, we also show that 5-HT dependent synaptic plasticity of the PFC is impaired in animals that are exposed to early-life chronic stress.


Neuronal Plasticity , Prefrontal Cortex , Serotonin , Animals , Rats , Long-Term Potentiation/physiology , Neuronal Plasticity/physiology , Prefrontal Cortex/growth & development , Receptors, Serotonin/metabolism , Serotonin/metabolism , Theta Rhythm
5.
Proc Natl Acad Sci U S A ; 119(2)2022 01 11.
Article En | MEDLINE | ID: mdl-34983868

Human learning is supported by multiple neural mechanisms that maturate at different rates and interact in mostly cooperative but also sometimes competitive ways. We tested the hypothesis that mature cognitive mechanisms constrain implicit statistical learning mechanisms that contribute to early language acquisition. Specifically, we tested the prediction that depleting cognitive control mechanisms in adults enhances their implicit, auditory word-segmentation abilities. Young adults were exposed to continuous streams of syllables that repeated into hidden novel words while watching a silent film. Afterward, learning was measured in a forced-choice test that contrasted hidden words with nonwords. The participants also had to indicate whether they explicitly recalled the word or not in order to dissociate explicit versus implicit knowledge. We additionally measured electroencephalography during exposure to measure neural entrainment to the repeating words. Engagement of the cognitive mechanisms was manipulated by using two methods. In experiment 1 (n = 36), inhibitory theta-burst stimulation (TBS) was applied to the left dorsolateral prefrontal cortex or to a control region. In experiment 2 (n = 60), participants performed a dual working-memory task that induced high or low levels of cognitive fatigue. In both experiments, cognitive depletion enhanced word recognition, especially when participants reported low confidence in remembering the words (i.e., when their knowledge was implicit). TBS additionally modulated neural entrainment to the words and syllables. These findings suggest that cognitive depletion improves the acquisition of linguistic knowledge in adults by unlocking implicit statistical learning mechanisms and support the hypothesis that adult language learning is antagonized by higher cognitive mechanisms.


Cognition/physiology , Learning/physiology , Prefrontal Cortex/physiology , Adolescent , Adult , Electroencephalography , Female , Humans , Language , Language Development , Linguistics , Male , Memory, Short-Term/physiology , Mental Recall , Prefrontal Cortex/growth & development , Transcranial Magnetic Stimulation , Young Adult
6.
J Neurosci ; 42(4): 601-618, 2022 01 26.
Article En | MEDLINE | ID: mdl-34844990

Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development.SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders.


Gene-Environment Interaction , Hippocampus/growth & development , Mental Disorders/genetics , Mental Disorders/physiopathology , Nerve Net/growth & development , Prefrontal Cortex/growth & development , Animals , Animals, Newborn , Disease Models, Animal , Excitatory Postsynaptic Potentials/physiology , Female , Hippocampus/chemistry , Male , Mental Disorders/psychology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Net/chemistry , Prefrontal Cortex/chemistry , Risk Factors
7.
Cells ; 10(11)2021 11 05.
Article En | MEDLINE | ID: mdl-34831259

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remain understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC) in HIV-1 transgenic (Tg) and control animals. Three putative neuroinflammatory markers (i.e., IL-1ß, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations and progressive synaptodendritic dysfunction, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. From a neurodevelopmental perspective, HIV-1 Tg rats exhibited prominent deficits in dendritic and synaptic pruning. With regards to progressive synaptodendritic dysfunction, HIV-1 Tg animals exhibited an age-related population shift towards dendritic spines with decreased volume, increased backbone length, and decreased head diameter; parameters associated with a more immature dendritic spine phenotype. There was no compelling evidence for neuroinflammation in the mPFC during early development. Collectively, progressive neuronal and dendritic spine dysmorphology herald synaptodendritic dysfunction as a key neural mechanism underlying chronic neurocognitive impairments in pALHIV.


HIV-1/physiology , Prefrontal Cortex/growth & development , Prefrontal Cortex/virology , Viral Proteins/metabolism , Aging/pathology , Animals , Dendritic Spines/metabolism , Models, Biological , Pyramidal Cells/pathology , Pyramidal Cells/virology , Rats, Inbred F344 , Rats, Transgenic , Synapses/metabolism
8.
Neurotoxicology ; 87: 167-173, 2021 12.
Article En | MEDLINE | ID: mdl-34599995

Phthalates are a class of endocrine disruptors found in a variety of consumer goods, and offspring can be exposed to these compounds during gestation and lactation. Our laboratory has found that perinatal exposure to an environmentally relevant mixture of phthalates resulted in a decrease in cognitive flexibility and in neuron number in the adult rat medial prefrontal cortex (mPFC). Here, we examine effects of phthalate treatment on prenatal cellular proliferation and perinatal apoptosis in the mPFC. To examine the phthalate effects on cellular proliferation, dams consumed 0, 1, or 5 mg/kg of the phthalate mixture daily from embryonic day 2 (E2) through the day of birth (P0), and on E16 and E17, they were injected with BrdU. The mPFC of offspring was analyzed on P5 and showed a decrease in labelled cells in the phthalate exposed groups. To examine whether changes in BrdU density observed on P5 were due to altered cell survival, cell death was measured on E18, P0, and P5 using a TUNEL assay in a separate cohort of prenatally exposed offspring. There was an increase in TUNEL labelled cells at E18 in the phthalate exposed groups. In the final experiment, dams consumed the phthalate mixture from E2 through P10, at which time mPFC tissue was stained with TUNEL. Phthalate treated subjects showed a higher density of apoptotic cells at P10. These results indicate both pre- and postnatal phthalate exposure increases apoptosis in the male and female rat mPFC. While the impact of phthalates on proliferation cannot be ruled out, these data do not allow for definitive conclusions.


Apoptosis/drug effects , Phthalic Acids/toxicity , Prefrontal Cortex/drug effects , Prenatal Exposure Delayed Effects/chemically induced , Animals , Animals, Newborn/growth & development , Cell Proliferation/drug effects , Female , In Situ Nick-End Labeling , Male , Prefrontal Cortex/embryology , Prefrontal Cortex/growth & development , Prefrontal Cortex/pathology , Pregnancy , Rats , Rats, Long-Evans
9.
Elife ; 102021 09 20.
Article En | MEDLINE | ID: mdl-34542408

Prioritizing memory for valuable information can promote adaptive behavior across the lifespan, but it is unclear how the neurocognitive mechanisms that enable the selective acquisition of useful knowledge develop. Here, using a novel task coupled with functional magnetic resonance imaging, we examined how children, adolescents, and adults (N = 90) learn from experience what information is likely to be rewarding, and modulate encoding and retrieval processes accordingly. We found that the ability to use learned value signals to selectively enhance memory for useful information strengthened throughout childhood and into adolescence. Encoding and retrieval of high- vs. low-value information was associated with increased activation in striatal and prefrontal regions implicated in value processing and cognitive control. Age-related increases in value-based lateral prefrontal cortex modulation mediated the relation between age and memory selectivity. Our findings demonstrate that developmental increases in the strategic engagement of the prefrontal cortex support the emergence of adaptive memory.


Adolescent Development , Association Learning , Child Development , Cognition , Memory , Neural Pathways/growth & development , Prefrontal Cortex/growth & development , Adolescent , Adult , Age Factors , Brain Mapping , Child , Female , Humans , Magnetic Resonance Imaging , Male , Neural Pathways/diagnostic imaging , Neuropsychological Tests , Prefrontal Cortex/diagnostic imaging , Young Adult
10.
Int J Mol Sci ; 22(16)2021 Aug 13.
Article En | MEDLINE | ID: mdl-34445411

BACKGROUND: The present study investigated the role of proteins from the bromodomain and extra-terminal (BET) family in schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia induced by prenatal methylazoxymethanol (MAM) administration (MAM-E17). METHODS: An inhibitor of BET proteins, JQ1, was administered during adolescence on postnatal days (P) 23-P29, and behavioural responses (sensorimotor gating, recognition memory) and prefrontal cortical (mPFC) function (long-term potentiation (LTP), molecular and proteomic analyses) studies were performed in adult males and females. RESULTS: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected animals of both sexes in the control but not MAM-treated groups and reduced behavioural responses in both sexes. An electrophysiological study showed LTP impairments only in male MAM-treated animals, and JQ1 did not affect LTP in the mPFC. In contrast, MAM did not affect activity-dependent gene expression, but JQ1 altered gene expression in both sexes. A proteomic study revealed alterations in MAM-treated groups mainly in males, while JQ1 affected both sexes. CONCLUSIONS: MAM-induced schizophrenia-like abnormalities were observed only in males, while adolescent JQ1 treatment affected memory recognition and altered the molecular and proteomic landscape in the mPFC of both sexes. Thus, transient adolescent inhibition of the BET family might prompt permanent alterations in the mPFC.


Azepines/administration & dosage , Methylazoxymethanol Acetate/analogs & derivatives , Prefrontal Cortex/growth & development , Schizophrenia/physiopathology , Triazoles/administration & dosage , Adolescent , Adolescent Development/drug effects , Animals , Azepines/pharmacology , Disease Models, Animal , Female , Gene Expression Regulation, Developmental/drug effects , Humans , Long-Term Potentiation/drug effects , Male , Methylazoxymethanol Acetate/toxicity , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Proteomics , Rats , Recognition, Psychology/drug effects , Schizophrenia/chemically induced , Schizophrenia/metabolism , Sex Characteristics , Triazoles/pharmacology
11.
Neuropharmacology ; 197: 108720, 2021 10 01.
Article En | MEDLINE | ID: mdl-34273386

Ionotropic glutamate receptors of the NMDA and AMPA subtypes transduce excitatory signaling on neurons in the prefrontal cortex (PFC) in support of cognitive flexibility. Cognitive flexibility is reliably observed to decline at advanced ages, coinciding with changes in PFC glutamate receptor expression and neuronal physiology. However, the relationship between age-related impairment of cognitive flexibility and changes to excitatory signaling on distinct classes of PFC neurons is not known. In this study, one cohort of young adult (4 months) and aged (20 months) male F344 rats were characterized for cognitive flexibility on an operant set-shifting task. Expression of the essential NMDAR subunit, NR1, was correlated with individual differences in set-shifting abilities such that lower NR1 in the aged PFC was associated with worse set-shifting. In contrast, lower expression of two AMPAR subunits, GluR1 and GluR2, was not associated with set-shift abilities in aging. As NMDARs are expressed by both pyramidal cells and fast-spiking interneurons (FSI) in PFC, whole-cell patch clamp recordings were performed in a second cohort of age-matched rats to compare age-associated changes on these neuronal subtypes. Evoked excitatory postsynaptic currents were generated using a bipolar stimulator while AMPAR vs. NMDAR-mediated components were isolated using pharmacological tools. The results revealed a clear increase in AMPA/NMDA ratio in FSIs that was not present in pyramidal neurons. Together, these data indicate that loss of NMDARs on interneurons in PFC contributes to age-related impairment of cognitive flexibility.


Aging/physiology , Cognitive Aging/physiology , Interneurons/physiology , Prefrontal Cortex/growth & development , Prefrontal Cortex/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Conditioning, Operant , Excitatory Postsynaptic Potentials/physiology , Male , Patch-Clamp Techniques , Prefrontal Cortex/metabolism , Psychomotor Performance/physiology , Pyramidal Cells/physiology , Rats , Rats, Inbred F344 , Receptors, AMPA/genetics , Receptors, AMPA/physiology , Receptors, N-Methyl-D-Aspartate/biosynthesis
12.
Neurochem Int ; 146: 105041, 2021 06.
Article En | MEDLINE | ID: mdl-33836218

Fluoxetine (FLX), a commonly used selective serotonin reuptake inhibitor, is often used to treat depression during pregnancy. However, prenatal exposure to FLX has been associated with a series of neuropsychiatric illnesses. The use of a rodent model can provide a clear indication as to whether prenatal exposure to SSRIs, independent of maternal psychiatric disorders or genetic syndromes, can cause long-term behavioral abnormalities in offspring. Thus, the present study aimed to explore whether prenatal FLX exposure causes long-term neurobehavioral effects, and identify the underlying mechanism between FLX and abnormal behaviors. In our study, 12/mg/kg/day of FLX or equal normal saline (NS) was administered to pregnant Sprague-Dawley (SD) rats (FLX = 30, NS = 27) on gestation day 11 till birth. We assessed the physical development and behavior of offspring, and in vivo magnetic resonance spectroscopy (MRS) was conducted to quantify biochemical alterations in the prefrontal cortex (PFC). Ex vivo measurements of brain serotonin level and a proteomic analysis were also undertaken. Our results showed that the offspring (male offspring in particular) of fluoxetine exposed mothers showed delayed physical development, increased anxiety-like behavior, and impaired social interaction. Moreover, down-regulation of 5-HT and SERT expression were identified in the PFC. We also found that prenatal FLX exposure significantly decreased NAA/tCr with 1H-MRS in the PFC of offspring. Finally, a proteomic study revealed sex-dependent differential protein expression. These findings may have translational importance suggesting that using SSRI medication alone in pregnant mothers may result in developmental delay in their offspring. Our results also help guide the choice of outcome measures in identifying of molecular and developmental mechanisms.


Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Prenatal Exposure Delayed Effects/metabolism , Selective Serotonin Reuptake Inhibitors/toxicity , Serotonin/metabolism , Social Interaction/drug effects , Animals , Female , Gene Expression , Male , Maternal Exposure/adverse effects , Prefrontal Cortex/growth & development , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/psychology , Rats , Rats, Sprague-Dawley
13.
PLoS One ; 16(2): e0243720, 2021.
Article En | MEDLINE | ID: mdl-33566829

Changing sleep rhythms in adolescents often lead to sleep deficits and a delay in sleep timing between weekdays and weekends. The adolescent brain, and in particular the rapidly developing structures involved in emotional control, are vulnerable to external and internal factors. In our previous study in adolescents at age 14, we observed a strong relationship between weekend sleep schedules and regional medial prefrontal cortex grey matter volumes. Here, we aimed to assess whether this relationship remained in this group of adolescents of the general population at the age of 16 (n = 101; mean age 16.8 years; 55% girls). We further examined grey matter volumes in the hippocampi and the amygdalae, calculated with voxel-based morphometry. In addition, we investigated the relationships between sleep habits, assessed with self-reports, and regional grey matter volumes, and psychological functioning, assessed with the Strengths and Difficulties Questionnaire and tests on working memory and impulsivity. Later weekend wake-up times were associated with smaller grey matter volumes in the medial prefrontal cortex and the amygdalae, and greater weekend delays in wake-up time were associated with smaller grey matter volumes in the right hippocampus and amygdala. The medial prefrontal cortex region mediated the correlation between weekend wake up time and externalising symptoms. Paying attention to regular sleep habits during adolescence could act as a protective factor against the emergence of psychopathology via enabling favourable brain development.


Brain/physiology , Emotions , Gray Matter/physiology , Sleep , Adolescent , Brain/growth & development , Female , Follow-Up Studies , Gray Matter/growth & development , Humans , Impulsive Behavior , Male , Memory, Short-Term , Prefrontal Cortex/growth & development , Prefrontal Cortex/physiology
14.
Nat Commun ; 12(1): 463, 2021 01 19.
Article En | MEDLINE | ID: mdl-33469025

Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain regions using single-cell long-read sequencing in mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 ( www.isoformAtlas.com ). Isoform tests for DIE show better performance than exon tests. We detect hundreds of DIE events traceable to cell types, often corresponding to functionally distinct protein isoforms. Mostly, one cell type is responsible for brain-region specific DIE. However, for fewer genes, multiple cell types influence DIE. Thus, regional identity can, although rarely, override cell-type specificity. Cell types indigenous to one anatomic structure display distinctive DIE, e.g. the choroid plexus epithelium manifests distinct transcription-start-site usage. Spatial transcriptomics and long-read sequencing yield a spatially resolved splicing map. Our methods quantify isoform expression with cell-type and spatial resolution and it contributes to further our understanding of how the brain integrates molecular and cellular complexity.


Alternative Splicing/physiology , Gene Expression Regulation, Developmental/physiology , Hippocampus/metabolism , Prefrontal Cortex/metabolism , Protein Isoforms/metabolism , Animals , Animals, Newborn , Computational Biology , Female , Hippocampus/cytology , Hippocampus/growth & development , Mice , Models, Animal , Prefrontal Cortex/cytology , Prefrontal Cortex/growth & development , Protein Isoforms/analysis , Protein Isoforms/genetics , Single-Cell Analysis/methods , Spatial Analysis
15.
Neurobiol Learn Mem ; 179: 107388, 2021 03.
Article En | MEDLINE | ID: mdl-33482320

The article reviews our studies of contextual fear conditioning (CFC) in rats during a period of development---Postnatal Day (PND) 17-33---that represents the late-infant, juvenile, and early-adolescent stages. These studies seek to acquire 'systems level' knowledge of brain and memory development and apply it to a rodent model of Fetal Alcohol Spectrum Disorder (FASD). This rodent model focuses on alcohol exposure from PND4-9, a period of brain development equivalent to the human third trimester, when neocortex, hippocampus, and cerebellum are especially vulnerable to adverse effects of alcohol. Our research emphasizes a variant of CFC, termed the Context Preexposure Facilitation Effect (CPFE, Fanselow, 1990), in which context representations incidentally learned on one occasion are retrieved and associated with immediate shock on a subsequent occasion. These representations can be encoded at the earliest developmental stage but seem not to be retained or retrieved until the juvenile period. This is associated with developmental differences in context-elicited expression, in prefrontal cortex, hippocampus, and amygdala, of immediate early genes (IEGs) that are implicated in long-term memory. Loss-of-function studies establish a functional role for these regions as soon as the CPFE emerges during ontogeny. In our rodent model of FASD, the CPFE is much more sensitive to alcohol dose than other commonly used cognitive tasks. This impairment can be reversed by acute administration during behavioral testing of drugs that enhance cholinergic function. This effect is associated with normalized IEG expression in prefrontal cortex during incidental context learning. In summary, our findings suggest that long-term memory of incidentally-learned context representations depends on prefrontal-hippocampal circuitry that is important both for the normative development of context conditioning and for its disruption by developmental alcohol exposure.


Behavior, Animal/physiology , Brain/growth & development , Conditioning, Classical/physiology , Fetal Alcohol Spectrum Disorders/physiopathology , Memory , Spatial Learning/physiology , Animals , Brain/physiology , Disease Models, Animal , Fear , Fetal Alcohol Spectrum Disorders/genetics , Gene Expression Regulation, Developmental , Genes, Immediate-Early/genetics , Growth and Development , Hippocampus/growth & development , Hippocampus/physiology , Learning , Prefrontal Cortex/growth & development , Prefrontal Cortex/physiology , Rats
16.
Neuroscientist ; 27(1): 10-29, 2021 02.
Article En | MEDLINE | ID: mdl-32441222

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.


Autism Spectrum Disorder , Nerve Net , Neuronal Plasticity , Peripheral Nervous System , Prefrontal Cortex , Animals , Autism Spectrum Disorder/etiology , Autism Spectrum Disorder/immunology , Autism Spectrum Disorder/physiopathology , Humans , Nerve Net/growth & development , Nerve Net/physiopathology , Neuronal Plasticity/physiology , Peripheral Nervous System/growth & development , Peripheral Nervous System/physiopathology , Prefrontal Cortex/growth & development , Prefrontal Cortex/physiopathology
17.
Cereb Cortex ; 31(2): 809-825, 2021 01 05.
Article En | MEDLINE | ID: mdl-32930336

While declines in inhibitory control, the capacity to suppress unwanted neurocognitive processes, represent a hallmark of healthy aging, whether this function is susceptible to training-induced plasticity in older populations remains largely unresolved. We addressed this question with a randomized controlled trial investigating the changes in behavior and electrical neuroimaging activity induced by a 3-week adaptive gamified Go/NoGo inhibitory control training (ICT). Performance improvements were accompanied by the development of more impulsive response strategies, but did not generalize to impulsivity traits nor quality of life. As compared with a 2-back working-memory training, the ICT in the older adults resulted in a purely quantitative reduction in the strength of the activity in a medial and ventrolateral prefrontal network over the 400 ms P3 inhibition-related event-related potentials component. However, as compared with young adults, the ICT induced distinct configurational modifications in older adults' 200 ms N2 conflict monitoring medial-frontal functional network. Hence, while older populations show preserved capacities for training-induced plasticity in executive control, aging interacts with the underlying plastic brain mechanisms. Training improves the efficiency of the inhibition process in older adults, but its effects differ from those in young adults at the level of the coping with inhibition demands.


Aging/physiology , Executive Function/physiology , Learning/physiology , Neuronal Plasticity/physiology , Prefrontal Cortex/physiology , Adult , Aged , Evoked Potentials , Female , Games, Experimental , Humans , Inhibition, Psychological , Male , Memory, Short-Term , Middle Aged , Nerve Net/growth & development , Nerve Net/physiology , Practice, Psychological , Prefrontal Cortex/growth & development , Psychomotor Performance/physiology , Young Adult
18.
Soc Cogn Affect Neurosci ; 16(3): 292-301, 2021 03 05.
Article En | MEDLINE | ID: mdl-33277895

We tested whether adolescents differ from each other in the structural development of the social brain and whether individual differences in social brain development predicted variability in friendship quality development. Adolescents (N = 299, Mage T1 = 13.98 years) were followed across three biannual waves. We analysed self-reported friendship quality with the best friend at T1 and T3, and bilateral measures of surface area and cortical thickness of the medial prefrontal cortex (mPFC), posterior superior temporal sulcus (pSTS), temporoparietal junction (TPJ) and precuneus across all waves. At the group level, growth curve models confirmed non-linear decreases of surface area and cortical thickness in social brain regions. We identified substantial individual differences in levels and change rates of social brain regions, especially for surface area of the mPFC, pSTS and TPJ. Change rates of cortical thickness varied less between persons. Higher levels of mPFC surface area and cortical thickness predicted stronger increases in friendship quality over time. Moreover, faster cortical thinning of mPFC surface area predicted a stronger increase in friendship quality. Higher levels of TPJ cortical thickness predicted lower friendship quality. Together, our results indicate heterogeneity in social brain development and how this variability uniquely predicts friendship quality development.


Brain Cortical Thickness , Brain/growth & development , Friends/psychology , Individuality , Adolescent , Brain/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Neuroimaging , Parietal Lobe/diagnostic imaging , Parietal Lobe/growth & development , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/growth & development , Temporal Lobe/diagnostic imaging , Temporal Lobe/growth & development
19.
Cereb Cortex ; 31(4): 2026-2037, 2021 03 05.
Article En | MEDLINE | ID: mdl-33279960

Visuospatial working memory (vsWM) requires information transfer among multiple cortical regions, from primary visual (V1) to prefrontal (PFC) cortices. This information is conveyed via layer 3 glutamatergic neurons whose activity is regulated by gamma-aminobutyric acid (GABA)ergic interneurons. In layer 3 of adult human neocortex, molecular markers of glutamate neurotransmission were lowest in V1 and highest in PFC, whereas GABA markers had the reverse pattern. Here, we asked if these opposite V1-visual association cortex (V2)-posterior parietal cortex (PPC)-PFC gradients across the vsWM network are present in layer 3 of monkey neocortex, when they are established during postnatal development, and if they are specific to this layer. We quantified transcript levels of glutamate and GABA markers in layers 3 and 6 of four vsWM cortical regions in a postnatal developmental series of 30 macaque monkeys. In adult monkeys, glutamate transcript levels in layer 3 increased across V1-V2-PPC-PFC regions, whereas GABA transcripts showed the opposite V1-V2-PPC-PFC gradient. Glutamate transcripts established adult-like expression patterns earlier during postnatal development than GABA transcripts. These V1-V2-PPC-PFC gradients and developmental patterns were less evident in layer 6. These findings demonstrate that expression of glutamate and GABA transcripts differs across cortical regions and layers during postnatal development, revealing potential molecular substrates for vsWM functional maturation.


Glutamic Acid/biosynthesis , Parietal Lobe/metabolism , Prefrontal Cortex/metabolism , Transcription, Genetic/physiology , Visual Cortex/metabolism , gamma-Aminobutyric Acid/biosynthesis , Age Factors , Animals , Excitatory Amino Acid Transporter 2/biosynthesis , Excitatory Amino Acid Transporter 2/genetics , Female , GABAergic Neurons/metabolism , Gene Expression , Glutamic Acid/genetics , Macaca mulatta , Parietal Lobe/growth & development , Prefrontal Cortex/growth & development , Receptors, GABA-A/biosynthesis , Receptors, GABA-A/genetics , Visual Cortex/growth & development , gamma-Aminobutyric Acid/genetics
20.
J Neurosci ; 41(2): 331-341, 2021 01 13.
Article En | MEDLINE | ID: mdl-33214318

In complex everyday environments, action selection is critical for optimal goal-directed behavior. This refers to the process of choosing a proper action from the range of possible alternatives. The neural mechanisms underlying action selection and how these are affected by normal aging remain to be elucidated. In the present cross-sectional study, we studied processes of effector selection during a multilimb reaction time task in a lifespan sample of healthy human adults (N = 89; 20-75 years; 48 males, 41 females). Participants were instructed to react as quickly and accurately as possible to visually cued stimuli representing single-limb or combined upper and/or lower limb motions. Diffusion MRI was used to study structural connectivity between prefrontal and striatal regions as critical nodes for action selection. Behavioral findings revealed that increasing age was associated with slowing of action selection performance. At the neural level, aging had a negative impact on prefronto-striatal connectivity. Importantly, mediation analyses revealed that the negative association between action selection performance and age was mediated by prefronto-striatal connectivity, specifically the connections between left rostral medial frontal gyrus and left nucleus accumbens as well as right frontal pole and left caudate. These results highlight the potential role of prefronto-striatal white matter decline in poorer action selection performance of older adults.SIGNIFICANCE STATEMENT As a result of enhanced life expectancy, researchers have devoted increasing attention to the study of age-related alterations in cognitive and motor functions. Here we study associations between brain structure and behavior to reveal the impact of central neural white matter changes as a function of normal aging on action selection performance. We demonstrate the critical role of a reduction in prefronto-striatal structural connectivity in accounting for action selection performance deficits in healthy older adults. Preserving this cortico-subcortical pathway may be critical for behavioral flexibility and functional independence in older age.


Neostriatum/anatomy & histology , Neostriatum/physiology , Neural Pathways/anatomy & histology , Neural Pathways/physiology , Prefrontal Cortex/anatomy & histology , Prefrontal Cortex/physiology , Adult , Aged , Aging/physiology , Caudate Nucleus/physiology , Cross-Sectional Studies , Cues , Decision Making , Diffusion Magnetic Resonance Imaging , Female , Humans , Male , Middle Aged , Movement/physiology , Neostriatum/growth & development , Neural Pathways/growth & development , Nucleus Accumbens/physiology , Photic Stimulation , Prefrontal Cortex/growth & development , Reaction Time/physiology , Young Adult
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