Dendrites contribute to the gradient of intrinsic timescales encompassing cortical and subcortical brain networks.

Introduction: Cytoarchitectonic studies have uncovered a correlation between higher levels of cortical hierarchy and reduced dendritic size. This hierarchical organization extends to the brain's timescales, revealing longer intrinsic timescales at higher hierarchical levels. However, estimating the contribution of single-neuron dendritic morphology to the hierarchy of timescales, which is typically characterized at a macroscopic level, remains challenging. Method: Here we mapped the intrinsic timescales of six functional networks using functional magnetic resonance imaging (fMRI) data, and characterized the influence of neuronal dendritic size on intrinsic timescales of brain regions, utilizing a multicompartmental neuronal modeling approach based on digitally reconstructed neurons. Results: The fMRI results revealed a hierarchy of intrinsic timescales encompassing both cortical and subcortical brain regions. The neuronal modeling indicated that neurons with larger dendritic structures exhibit shorter intrinsic timescales. Together these findings highlight the contribution of dendrites at the neuronal level to the hierarchy of intrinsic timescales at the whole-brain level. Discussion: This study sheds light on the intricate relationship between neuronal structure, cytoarchitectonic maps, and the hierarchy of timescales in the brain.

Neonatal Cannabidiol Exposure Impairs Spatial Memory and Disrupts Neuronal Dendritic Morphology in Young Adult Rats.

Introduction: Early life is a sensitive period for brain development. Perinatal exposure to cannabis is increasingly linked to disruption of neurodevelopment; however, research on the effects of cannabidiol (CBD) on the developing brain is scarce. In this study, we aim to study the developmental effects of neonatal CBD exposure on behavior and dendritic architecture in young adult rats. Materials and Methods: Male and female neonatal Sprague Dawley rats were treated with CBD (50 mg/kg) intraperitoneally on postnatal day (PND) 1, 3, and 5 and evaluated for behavioral and neuronal morphological changes during early adulthood. Rats were subjected to a series of behavioral tasks to evaluate long-term effects of neonatal CBD exposure, including the Barnes maze, open field, and elevated plus maze paradigms to assess spatial memory and anxiety-like behavior. Following behavioral evaluation, animals were sacrificed, and neuronal morphology of the cortex and hippocampus was assessed using Golgi-Cox (GC) staining. Results: Rats treated with CBD displayed a sexually dimorphic response in spatial memory, with CBD-treated females developing a deficit but not males. CBD did not elicit alterations in anxiety-like behavior in either sex. Neonatal CBD caused an overall decrease in dendritic length and spine density (apical and basal) in cortical and hippocampal neurons in both sexes. Sholl analysis also revealed a decrease in dendritic intersections in the cortex and hippocampus, indicating reduced dendritic arborization. Conclusions: This study provides evidence that neonatal CBD exposure perturbs normal brain development and leads to lasting alterations in spatial memory and neuronal dendrite morphology in early adulthood, with sex-dependent sensitivity.

Dendritic Morphology of Developing Hippocampal Neurons in Cyp11a1 Null Mice.

INTRODUCTION: Neurosteroids have a variety of neurological functions, such as neurite growth, neuroprotection, myelination, and neurogenesis. P450scc, encoded by CYP11A1 gene, is the cholesterol side chain cleavage enzyme that catalyzes the first and rate-limiting step in steroidogenesis. In this study, we examine the dendritic morphology in developing hippocampal neurons of Cyp11a1 null mice at P15, a critical period for synapse formation and maturation. METHODS: Knockout mice were maintained until P15 with hormone administration. The Golgi-Cox method stained CA1 and CA3 pyramidal neurons in the hippocampus to reveal dendritic morphology. RESULTS: We demonstrated that Cyp11a1 null mice usually die within 7 days after birth and thus collected brain samples at postnatal day 5 (P5) for examination. There was significant shrinkage of dendrite size and diminishment of dendritic branching in CA1 and CA3 pyramidal neurons in the hippocampus of Cyp11a1 null mice, suggesting a developmental delay. We wonder if this delay may catch up later in life. Since the age of P15 is a critical period for synapse formation and maturation, the Cyp11a1 null mice were rescued by receiving hormone administration until P15 that the dendritic morphology in the developing hippocampal neurons could be examined. The results indicated that the total dendritic length, the number of dendritic branches, as well as dendritic arborization in the CA1 and CA3 pyramidal neurons are significantly decreased in P15 knockout mice when compared to the wild type. The spine densities were also significantly decreased. In addition, the Western blot analysis revealed decreased PSD-95 expression levels in the knockout mice compared to the wild type at P15. CONCLUSION: These results suggested that Cyp11a1 deficiency impairs the dendritic structures in the developing hippocampal pyramidal neurons.

Individual NMDA receptor GluN2 subunit signaling domains differentially regulate the postnatal maturation of hippocampal excitatory synaptic transmission and plasticity but not dendritic morphology.

N-methyl-d-aspartate receptors (NMDARs) at hippocampal excitatory synapses undergo a late postnatal shift in subunit composition, from an initial prevalence of GluN2B subunit incorporation to a later predominance of GluN2A. This GluN2B to GluN2A shift alters NMDAR calcium conductance dynamics and intracellular molecular signaling that are individually regulated by distinct GluN2 signaling domains and temporally align with developmental alterations in dendritic and synaptic plasticity. However, the impacts of individual GluN2B to GluN2A signaling domains on neuronal development remain unknown. Ionotropic and intracellular signaling domains of GluN2 subunits were separated by creating chimeric GluN2 subunits that were expressed in two transgenic mouse lines. Western blot and immunoprecipitation revealed that roughly one third of native synaptic NMDARs were replaced by transformed NMDARs without altering total synaptic NMDAR content. Schaffer collateral synaptic strength was transiently increased in acutely prepared hippocampal slices at just over 3 weeks of age in animals overexpressing the GluN2B carboxy terminus. Long-term potentiation (LTP) induction following lower frequency stimulation was regulated by GluN2 ionotropic signaling domains in an age-dependent manner and LTP maintenance was enhanced by overexpression of the GluN2B CTD in mature animals. After higher frequency stimulation, the induction and maintenance of LTP were increased in young adult animals overexpressing the GluN2B ionotropic signaling domains but reduced in juveniles just over 3 weeks of age. Confocal imaging of green fluorescent protein (GFP)- labeled CA1 pyramidal neurons revealed no alterations in dendritic morphology or spine density in mice expressing chimeric GluN2 subunits. These results illustrate how individual GluN2 subunit signaling domains do or do not control physiological and morphological development of hippocampal excitatory neurons and better clarify the neurobiological factors that govern hippocampal maturation. SIGNIFICANCE STATEMENT: A developmental reduction in the magnitude of hippocampal long-term synaptic potentiation (LTP) and a concomitant improvement in spatial maze performance coincide with greater incorporation of GluN2A subunits into synaptic NMDARs. Corroborating our prior discovery that overexpression of GluN2A-type ionotropic signaling domains enables context-based navigation in immature mice, GluN2A-type ionotropic signaling domain overexpression reduces LTP induction threshold and magnitude in immature mice. Also, we previously found that GluN2B carboxy terminal domain (CTD) overexpression enhances long-term spatial memory in mature mice and now report that the GluN2B CTD is associated with greater amplitude of LTP after induction in mature mice. Thus, the late postnatal maturation of context encoding likely relies on a shift toward GluN2A-type ionotropic signaling and a reduction in the threshold to induce LTP while memory consolidation and LTP maintenance are regulated by GluN2B subunit CTD signaling.

Tenuifolin improves learning and memory by regulating long-term potentiation and dendritic structure of hippocampal CA1 area in healthy female mice but not male mice.

Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment.

Sex-specific dendritic morphology of hippocampal pyramidal neurons in the adolescent and young adult rats.

CA1 and CA3 pyramidal neurons are the major sources of hippocampal efferents. The structural features of these neurons are presumed to be involved in various normal/abnormal cognitive and emotional outcomes by influencing the pattern of synaptic inputs and neuronal signal processing. Although many studies have described hippocampal structure differences between males and females, these reports mainly focused on gross anatomical features in adult or aged models, and such distinctions on neuronal morphology and dendritic spine density during adolescence, a period of high vulnerability to neurodevelopmental disorders, have received much less attention. In this work, we analyzed dendritic architecture and density of spines in CA1 and CA3 neurons of male and female rats in early adolescence (postnatal day, PND 40) and compared them with those in late adolescence/young adulthood (PND 60). On PND 40, CA1 neurons of male rats showed more Sholl intersections and spine density in apical and basal dendrites compared to those in females. The Sholl intersections in basal dendrites of CA3 neurons were also more in males, whereas the number of apical dendrite intersections was not significantly different between sexes. In male rats, there was a notable decrease in the number of branch and terminal points in the basal dendrite of CA1 neurons of young adults when compared to their sex-matched adolescent rats. On the other hand, CA1 neurons in young adult females also showed more Sholl intersections in apical and basal dendrites compared to adolescent females. Meanwhile, the total cable length, the number of branches, and terminal points of apical dendrites in CA3 neurons also exhibited a significant reduction in young adult male rats compared to their sex-matched adolescents. In young adult rats, both apical and basal dendrites of CA3 neurons in males showed fewer intersections with Sholl circles, but there were no significant differences in dendritic spine density or count estimation between males and females. On the other hand, young adult female rats had more Sholl intersections and dendritic spine count on the basal dendrites of CA3 neurons compared to adolescent females. Although no significant sex- and age-dependent difference in neuronal density was detected in CA1 and CA3 subareas, CA3 pyramidal neurons of both male and female rats showed reduced soma area compared to adolescent rats. Our findings show that the sex differences in the dendritic structure of CA1 and CA3 neurons vary by age and also by the compartments of dendritic arbors. Such variations in the morphology of hippocampal pyramidal neurons may take part as a basis for normal cognitive and affective differences between the sexes, as well as distinct sensitivity to interfering factors and the prevalence of neuropsychological diseases.

Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A.

In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high γ oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high γ. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments.

Comparative features of calretinin, calbindin, and parvalbumin expressing interneurons in mouse and monkey primary visual and frontal cortices.

Fundamental differences in excitatory pyramidal cells across cortical areas and species highlight the implausibility of extrapolation from mouse to primate neurons and cortical networks. Far less is known about comparative regional and species-specific features of neurochemically distinct cortical inhibitory interneurons. Here, we quantified the density, laminar distribution, and somatodendritic morphology of inhibitory interneurons expressing one or more of the calcium-binding proteins (CaBPs) (calretinin [CR], calbindin [CB], and/or parvalbumin [PV]) in mouse (Mus musculus) versus rhesus monkey (Macaca mulatta) in two functionally and cytoarchitectonically distinct regions-the primary visual and frontal cortical areas-using immunofluorescent multilabeling, stereological counting, and 3D reconstructions. There were significantly higher densities of CB+ and PV+ neurons in visual compared to frontal areas in both species. The main species difference was the significantly greater density and proportion of CR+ interneurons and lower extent of CaBP coexpression in monkey compared to mouse cortices. Cluster analyses revealed that the somatodendritic morphology of layer 2-3 inhibitory interneurons is more dependent on CaBP expression than on species and area. Only modest effects of species were observed for CB+ and PV+ interneuron morphologies, while CR+ neurons showed no difference. By contrast to pyramidal cells that show highly distinctive area- and species-specific features, here we found more subtle differences in the distribution and features of interneurons across areas and species. These data yield insight into how nuanced differences in the population organization and properties of neurons may underlie specializations in cortical regions to confer species- and area-specific functional capacities.

Neuronal silence as a prosurvival factor for adult-born olfactory bulb interneurons.

Adult-born cells, arriving daily into the rodent olfactory bulb, either integrate into the neural circuitry or get eliminated. However, whether these two populations differ in their morphological or functional properties remains unclear. Using longitudinal in vivo two-photon imaging, we monitored dendritic morphogenesis, odor-evoked responsiveness, ongoing Ca2+ signaling, and survival/death of adult-born juxtaglomerular neurons (abJGNs). We found that the maturation of abJGNs is accompanied by a significant reduction in dendritic complexity, with surviving and subsequently eliminated cells showing similar degrees of dendritic remodeling. Surprisingly, ∼63% of eliminated abJGNs acquired odor responsiveness before death, with amplitudes and time courses of odor-evoked responses similar to those recorded in surviving cells. However, the subsequently eliminated cell population exhibited significantly higher ongoing Ca2+ signals, with a difference visible even 10 days before death. Quantitative supervised machine learning analysis revealed a relationship between the abJGNs' activity and survival probability, with low neuronal activity being supportive for survival.

Integrin ß3 regulates apical dendritic morphology of pyramidal neurons throughout hippocampal CA3.

In excitatory hippocampal pyramidal neurons, integrin ß3 is critical for synaptic maturation and plasticity in vitro. Itgb3 is a potential autism susceptibility gene that regulates dendritic morphology in the cerebral cortex in a cell-specific manner. However, it is unknown what role Itgb3 could have in regulating hippocampal pyramidal dendritic morphology in vivo, a key feature that is aberrant in many forms of autism and intellectual disability. We found that Itgb3 mRNA is expressed in the stratum pyramidale of CA3. We examined the apical dendritic morphology of CA3 hippocampal pyramidal neurons in conditional Itgb3 knockouts and controls, utilizing the Thy1-GFP-M line. We fully reconstructed the apical dendrite of each neuron and determined each neuron's precise location along the dorsoventral, proximodistal, and radial axes of the stratum pyramidale. We found a very strong effect for Itgb3 expression on CA3 apical dendritic morphology: neurons from conditional Itgb3 knockouts had longer and thinner apical dendrites than controls, particularly in higher branch orders. We also assessed potential relationships between pairs of topographic or morphological variables, finding that most variable pairs were free from any linear relationships to each other. We also found that some neurons from controls, but not conditional Itgb3 knockouts, had a graded pattern of overall diameter along the dorsoventral and proximodistal axes of the stratum pyramidale of CA3. Taken together, Itgb3 is essential for constructing normal dendritic morphology in pyramidal neurons throughout CA3.