Showing papers by "Patrick R. Hof published in 2020"

Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

Abstract: The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolutionary distance and is consistent between the transcriptome and epigenome. The core conserved molecular identity of neuronal and non-neuronal types allowed the generation of a cross-species consensus cell type classification and inference of conserved cell type properties across species. Despite overall conservation, many species specializations were apparent, including differences in cell type proportions, gene expression, DNA methylation, and chromatin state. Few cell type marker genes were conserved across species, providing a short list of candidate genes and regulatory mechanisms responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allowed the Patch-seq identification of layer 5 (L5) corticospinal Betz cells in non-human primate and human and characterization of their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons

Abstract: The neocortex is disproportionately expanded in human compared to mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers that selectively make connections within the cortex and other telencephalic structures. Single-cell transcriptomic analyses of human and mouse cortex show an increased diversity of glutamatergic neuron types in supragranular cortex in human and pronounced gradients as a function of cortical depth. To probe the functional and anatomical correlates of this transcriptomic diversity, we describe a robust Patch-seq platform using neurosurgically-resected human tissues. We characterize the morphological and physiological properties of five transcriptomically defined human glutamatergic supragranular neuron types. Three of these types have properties that are specialized compared to the more homogeneous properties of transcriptomically defined homologous mouse neuron types. The two remaining supragranular neuron types, located exclusively in deep layer 3, do not have clear mouse homologues in supragranular cortex but are transcriptionally most similar to deep layer mouse intratelencephalic-projecting neuron types. Furthermore, we reveal the transcriptomic types in deep layer 3 that express high levels of non-phosphorylated heavy chain neurofilament protein that labels long-range neurons known to be selectively depleted in Alzheimer9s disease. Together, these results demonstrate the power of transcriptomic cell type classification, provide a mechanistic underpinning for increased complexity of cortical function in human cortical evolution, and implicate discrete transcriptomic cell types as selectively vulnerable in disease.

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

Abstract: Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [18F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [18F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

The functional anatomy of cognitive control: A domain-general brain network for uncertainty processing.

Abstract: Cognitive control is the coordination of mental operations under conditions of uncertainty in accordance with goal-directed behaviors, and plays a key role in the domains of executive control, working memory, and decision-making. Although there is emerging evidence of common involvement of the cognitive control network (CCN) of the brain in these domains, this network has mostly been linked to the processing of conflict, which is just one case of an increase in uncertainty. Here, we conducted an activation-likelihood-estimation-based large-scale meta-analysis of 289 functional magnetic resonance imaging studies in the three domains to examine the common involvement of the CCN in uncertainty processing by contrasting the high-uncertainty versus low-uncertainty conditions. We found a general association between increase in uncertainty and an activation increase in regions of the CCN, including the frontoparietal network (comprising the frontal eye fields, the areas near and along the intraparietal sulcus, and the dorsolateral prefrontal cortex), the cingulo-opercular network (including the anterior cingulate cortex extending to the supplementary motor area, and the anterior insular cortex), and a subcortical structure (the striatum). These results demonstrate that the CCN is a domain-general construct underlying uncertainty processing to support goal-directed behaviors.

The Role of Copper in Tau-Related Pathology in Alzheimer's Disease

Abstract: All tauopathies, including Alzheimer's disease (AD), are characterized by the intracellular accumulation of abnormal forms of tau protein in neurons and glial cells, which negatively affect microtubule stability. Under physiological conditions, tubulin-associated unit (Tau) protein is intrinsically disordered, almost without secondary structure, and is not prone to aggregation. In AD, it assembles, and forms paired helical filaments (PHFs) that further build-up neurofibrillary tangles (NFTs). Aggregates are composed of hyperphosphorylated tau protein that is more prone to aggregation. The pathology of AD is also linked to disturbed copper homeostasis, which promotes oxidative stress (OS). Copper imbalance is widely observed in AD patients. Deregulated copper ions may initiate and exacerbate tau hyperphosphorylation and formation of β-sheet-rich tau fibrils that ultimately contribute to synaptic failure, neuronal death, and cognitive decline observed in AD patients. The present review summarizes factors affecting the process of tau aggregation, conformational changes of small peptide sequences in the microtubule-binding domain required for these motifs to act as seeding sites in aggregation, and the role of copper in OS induction, tau hyperphosphorylation and tau assembly. A better understanding of the various factors that affect tau aggregation under OS conditions may reveal new targets and novel pharmacological approaches for the therapy of AD.

IL-1β, IL-6, IL-10, and TNFα Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer's Disease Pathology.

Abstract: Background: Neuroinflammation plays an important role in Alzheimer's disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α (TNFα) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β-1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896), and TNFα -308A/G (rs1800629) polymorphisms with AD. ----- Objective: We aimed to investigate whether people with certain IL-1α, IL-1β, IL-6, IL-10, and TNFα genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid-β1-42, total tau (t-tau), tau phosphorylated at Thr 181 (p-tau181), Ser 199 (p-tau199), and Thr 231 (p-tau231), and visinin-like protein 1 (VILIP-1). ----- Methods: The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. The polymorphisms were determined using real-time polymerase chain reaction. Levels of CSF biomarkers were determined by enzyme-linked immunosorbent assay. ----- Results: A significant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G, and GG TNFα -308A/G genotype. ----- Conclusion: These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G), and TNFIα (-308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD.

Invariant Synapse Density and Neuronal Connectivity Scaling in Primate Neocortical Evolution

Abstract: Synapses are involved in the communication of information from one neuron to another. However, a systematic analysis of synapse density in the neocortex from a diversity of species is lacking, limiting what can be understood about the evolution of this fundamental aspect of brain structure. To address this, we quantified synapse density in supragranular layers II-III and infragranular layers V-VI from primary visual cortex and inferior temporal cortex in a sample of 25 species of primates, including humans. We found that synapse densities were relatively constant across these levels of the cortical visual processing hierarchy and did not significantly differ with brain mass, varying by only 1.9-fold across species. We also found that neuron densities decreased in relation to brain enlargement. Consequently, these data show that the number of synapses per neuron significantly rises as a function of brain expansion in these neocortical areas of primates. Humans displayed the highest number of synapses per neuron, but these values were generally within expectations based on brain size. The metabolic and biophysical constraints that regulate uniformity of synapse density, therefore, likely underlie a key principle of neuronal connectivity scaling in primate neocortical evolution.

PI3K/Akt and ERK1/2 Signalling Are Involved in Quercetin-Mediated Neuroprotection against Copper-Induced Injury.

Abstract: Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when present in excess by promoting production of reactive oxygen species (ROS). The aim of the present study was to investigate potential benefits of flavonoid quercetin against copper-induced toxicity. Results obtained with MTT assay indicate that the effects of quercetin are determined by the severity of the toxic insult. In moderately injured P19 neuronal cells, concomitant treatment with 150 μM quercetin improved viability by preventing ROS formation, caspase-3 activation, and chromatin condensation. Western blot analysis revealed that quercetin reduced copper-induced increase in p53 upregulated modulator of apoptosis (PUMA) expression and promoted upregulation of nucleoside diphosphate kinase NME1. Levels of p53 and Bax proteins were not affected by both copper and quercetin. UO126 and wortmannin, inhibitors of ERK1/2 and PI3K/Akt signalling pathways, respectively, prevented neuroprotective effects of quercetin. In severely injured neurons, 30 μM quercetin exerted strong prooxidative action and exacerbated cytotoxic effects of copper, whereas 150 μM quercetin failed to affect neuronal survival. These results demonstrate the dual nature of quercetin action in copper-related neurodegeneration. Hence, they are relevant in the context of considering quercetin as a possible therapeutic for neuroprotection and imply that detailed pharmacological and toxicological studies must be carried out for natural compounds capable of acting both as antioxidants and prooxidants.

Supramodal Mechanisms of the Cognitive Control Network in Uncertainty Processing

Abstract: Information processing under conditions of uncertainty requires the involvement of cognitive control. Despite behavioral evidence of the supramodal function (i.e., independent of sensory modality) of cognitive control, the underlying neural mechanism needs to be directly tested. This study used functional magnetic imaging together with visual and auditory perceptual decision-making tasks to examine brain activation as a function of uncertainty in the two stimulus modalities. The results revealed a monotonic increase in activation in the cortical regions of the cognitive control network (CCN) as a function of uncertainty in the visual and auditory modalities. The intrinsic connectivity between the CCN and sensory regions was similar for the visual and auditory modalities. Furthermore, multivariate patterns of activation in the CCN predicted the level of uncertainty within and across stimulus modalities. These findings suggest that the CCN implements cognitive control by processing uncertainty as abstract information independent of stimulus modality.

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective.

Abstract: The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs) migration, as these cells differentiate at their final destinations and proliferate into different tissues whose activity is reduced by domestication. Comparing the phenotypic characteristics of modern and prehistoric man, it is clear that during their recent evolutionary past, humans also went through a process of self-domestication with a simultaneous prolongation of the period of socialization. This has led to the development of social abilities and skills, especially language, as well as neoteny. Disorders of neural crest cell development and migration lead to many different conditions such as Waardenburg syndrome, Hirschsprung disease, fetal alcohol syndrome, DiGeorge and Treacher-Collins syndrome, for which the mechanisms are already relatively well-known. However, for others, such as Williams-Beuren syndrome and schizophrenia that have the characteristics of hyperdomestication, and autism spectrum disorders, and 7dupASD syndrome that have the characteristics of hypodomestication, much less is known. Thus, deciphering the biological determinants of disordered self-domestication has great potential for elucidating the normal and disturbed ontogenesis of humans, as well as for the understanding of evolution of mammals in general.

Neuron loss associated with age but not Alzheimer's disease pathology in the chimpanzee brain

Abstract: In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an in...

Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

Abstract: The noradrenergic and dopaminergic systems are affected in Alzheimer’s disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine - hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called –1021C/T or –970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181, p-tau199, and p-tau231), amyloid-42 (A42), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in A42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. A42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD.

Brain gyrification in wild and domestic canids: Has domestication changed the gyrification index in domestic dogs?

Abstract: Over the last 15 years, research on canid cognition has revealed that domestic dogs possess a surprising array of complex socio‐cognitive skills pointing to the possibility that the domestication process might have uniquely altered their brains; however, we know very little about how evolutionary processes (natural or artificial) might have modified underlying neural structure to support species‐specific behaviors Evaluating the degree of cortical folding (ie, gyrification) within canids may prove useful, as this parameter is linked to functional variation of the cerebral cortex Using quantitative magnetic resonance imaging to investigate the impact of domestication on the canine cortical surface, we compared the gyrification index (GI) in 19 carnivore species, including six wild canid and 13 domestic dog individuals We also explored correlations between global and local GI with brain mass, cortical thickness, white and grey matter volume and surface area Our results indicated that GI values for domestic dogs are largely consistent with what would be expected for a canid of their given brain mass, although more variable than that observed in wild canids We also found that GI in canids is positively correlated with cortical surface area, cortical thickness and total cortical grey matter volumes While we found no evidence of global differences in GI between domestic and wild canids, certain regional differences in gyrification were observed

Evolution of regulatory signatures in primate cortical neurons at cell-type resolution.

Abstract: The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell-type-specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee, and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype-specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder, and drug addiction. We observe preferential evolutionary divergence in neuron subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergoes subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type-dependent gene-expression programs, and provides a resource for further exploration of human brain evolution and function.

Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

Abstract: Deletion or mutations of SHANK3 lead to Phelan–McDermid syndrome and monogenic forms of autism spectrum disorder (ASD). SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency of Shank3 in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC). We assessed dendrite and spine morphology and spine density in mPFC layer III neurons in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses. Basal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes in Shank3-Het compared to WT and Shank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses in Shank3-Het rats, but not Shank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger in Shank3-Het rats compared to Shank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan–McDermid syndrome. The Shank3 deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in male Shank3-deficient rats. We observed increased HD and PSD area in Shank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan–McDermid syndrome.

Adolescent frontal top-down neurons receive heightened local drive to establish adult attentional behavior in mice.

Abstract: Frontal top-down cortical neurons projecting to sensory cortical regions are well-positioned to integrate long-range inputs with local circuitry in frontal cortex to implement top-down attentional control of sensory regions. How adolescence contributes to the maturation of top-down neurons and associated local/long-range input balance, and the establishment of attentional control is poorly understood. Here we combine projection-specific electrophysiological and rabies-mediated input mapping in mice to uncover adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are highly functionally integrated into local excitatory circuitry and have heightened activity compared to adulthood. Chemogenetic suppression of top-down neuron activity selectively during adolescence, but not later periods, produces long-lasting visual attentional behavior deficits, and results in excessive loss of local excitatory inputs in adulthood. Our study reveals an adolescent sensitive period when top-down neurons integrate local circuits with long-range connectivity to produce attentional behavior. Frontal top-down cortical neurons implement top-down attentional control of sensory regions. The authors reveal adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are functionally integrated into local excitatory circuitry.

Evolutionary shifts dramatically reorganized the human hippocampal complex.

Abstract: The hippocampal complex (HC) is central to long-term memory storage and retrieval as well as spatial navigation across many species. Notably, humans appear to have greatly enhanced and possibly unique HC-mediated capacities such as constructive episodic simulation. Key studies have shown that the human HC is disproportionately large amongst hominoids, but much remains unknown at the levels of substructural evolutionary reorganization and ecological selection. Here, we calculated relative sizes of 12 HC subregions in a diverse sample of 44 primate species. We then used a Bayesian phylogenetic method, selective regime analysis, to identify 27 separate evolutionary shifts in HC organization across 65 million years of primate evolution. Additionally, a series of multivariate phylogenetic regressions using HC-related ecological variables as predictors (Diet Breadth, Population Density, Group Size, Home Range Size, and Residual Home Range) revealed that relative fascia dentata and CA1 size were both significantly predicted by species' home range size (after correcting for body size). However, perhaps the most notable finding of this study was that the shifts in HC size and subregional organization in the human lineage were the largest seen in all of primate evolution, rendering modern humans with a HC that is a clear outlier amongst all nonhuman primates investigated here. Given the extensive literature confirming the relationship between HC organization and function, these selective shifts are likely to have played a significant role in the emergence of human-specific capacities, such as constructive episodic simulation.

Quantification of neurons in the hippocampal formation of chimpanzees: comparison to rhesus monkeys and humans.

Abstract: The hippocampal formation is important for higher brain functions such as spatial navigation and the consolidation of memory, and it contributes to abilities thought to be uniquely human, yet little is known about how the human hippocampal formation compares to that of our closest living relatives, the chimpanzees. To gain insight into the comparative organization of the hippocampal formation in catarrhine primates, we quantified neurons stereologically in its major subdivisions—the granular layer of the dentate gyrus, CA4, CA2-3, CA1, and the subiculum—in archival brain tissue from six chimpanzees ranging from 29 to 43 years of age. We also sought evidence of Aβ deposition and hyperphosphorylated tau in the hippocampus and adjacent neocortex. A 42-year-old animal had moderate cerebral Aβ-amyloid angiopathy and tauopathy, but Aβ was absent and tauopathy was minimal in the others. Quantitatively, granule cells of the dentate gyrus were most numerous, followed by CA1, subiculum, CA4, and CA2-3. In the context of prior investigations of rhesus monkeys and humans, our findings indicate that, in the hippocampal formation as a whole, the proportions of neurons in CA1 and the subiculum progressively increase, and the proportion of dentate granule cells decreases, from rhesus monkeys to chimpanzees to humans. Because CA1 and the subiculum engender key hippocampal projection pathways to the neocortex, and because the neocortex varies in volume and anatomical organization among these species, these findings suggest that differences in the proportions of neurons in hippocampal subregions of catarrhine primates may be linked to neocortical evolution.

The brain of the African wild dog. II. The olfactory system.

Abstract: Employing a range of neuroanatomical stains, we detail the organization of the main and accessory olfactory systems of the African wild dog. The organization of both these systems follow that typically observed in mammals, but variations of interest were noted. Within the main olfactory bulb, the size of the glomeruli, at approximately 350 µm in diameter, are on the larger end of the range observed across mammals. In addition, we estimate that approximately 3,500 glomeruli are present in each main olfactory bulb. This larger main olfactory bulb glomerular size and number of glomeruli indicates that enhanced peripheral processing of a broad range of odorants is occurring in the main olfactory bulb of the African wild dog. Within the accessory olfactory bulb, the glomeruli did not appear distinct, rather forming a homogenous syncytia-like arrangement as seen in the domestic dog. In addition, the laminar organization of the deeper layers of the accessory olfactory bulb was indistinct, perhaps as a consequence of the altered architecture of the glomeruli. This arrangement of glomeruli indicates that rather than parcellating the processing of semiochemicals peripherally, these odorants may be processed in a more nuanced and combinatorial manner in the periphery, allowing for more rapid and precise behavioural responses as required in the highly social group structure observed in the African wild dog. While having a similar organization to that of other mammals, the olfactory system of the African wild dog has certain features that appear to correlate to their environmental niche.

Brain of the African wild dog. I. Anatomy, architecture, and volumetrics.

Abstract: The African wild dog is endemic to sub-Saharan Africa and belongs to the family Canidae which includes domestic dogs and their closest relatives (i.e., wolves, coyotes, jackals, dingoes, and foxes). The African wild dog is known for its highly social behavior, co-ordinated pack predation, and striking vocal repertoire, but little is known about its brain and whether it differs in any significant way from that of other canids. We employed gross anatomical observation, magnetic resonance imaging, and classical neuroanatomical staining to provide a broad overview of the structure of the African wild dog brain. Our results reveal a mean brain mass of 154.08 g, with an encephalization quotient of 1.73, indicating that the African wild dog has a relatively large brain size. Analysis of the various structures that comprise their brains and their topological inter-relationships, as well as the areas and volumes of the corpus callosum, ventricular system, hippocampus, amygdala, cerebellum and the gyrification index, all reveal that the African wild dog brain is, in general, similar to that of other mammals, and very similar to that of other carnivorans. While at this level of analysis we do not find any striking specializations within the brain of the African wild dog, apart from a relatively large brain size, the observations made indicate that more detailed analyses of specific neural systems, particularly those involved in sensorimotor processing, sociality or cognition, may reveal features that are either unique to this species or shared among the Canidae to the exclusion of other Carnivora.

The brain of the African wild dog. III. The auditory system

Abstract: The large external pinnae and extensive vocal repertoire of the African wild dog (Lycaon pictus) has led to the assumption that the auditory system of this unique canid may be specialized. Here, using cytoarchitecture, myeloarchitecture, and a range of immunohistochemical stains, we describe the systems-level anatomy of the auditory system of the African wild dog. We observed the cochlear nuclear complex, superior olivary nuclear complex, lateral lemniscus, inferior colliculus, medial geniculate body, and auditory cortex all being in their expected locations, and exhibiting the standard subdivisions of this system. While located in the ectosylvian gyri, the auditory cortex includes several areas, resembling the parcellation observed in cats and ferrets, although not all of the auditory areas known from these species could be identified in the African wild dog. These observations suggest that, broadly speaking, the systems-level anatomy of the auditory system, and by extension the processing of auditory information, within the brain of the African wild dog closely resembles that observed in other carnivores. Our findings indicate that it is likely that the extraction of the semantic content of the vocalizations of African wild dogs, and the behaviors generated, occurs beyond the classically defined auditory system, in limbic or association neocortical regions involved in cognitive functions. Thus, to obtain a deeper understanding of how auditory stimuli are processed, and how communication is achieved, in the African wild dog compared to other canids, cortical regions beyond the primary sensory areas will need to be examined in detail.

Adolescent frontal top-down neurons receive heightened local drive to establish adult attentional behavior in mice

Abstract: Frontal top-down cortical neurons projecting to sensory cortical regions are well-positioned to integrate long-range inputs with local circuitry in frontal cortex to implement top-down attentional control of sensory regions. How adolescence contributes to the maturation of top-down neurons and associated local/long-range input balance, and the establishment of attentional control is poorly understood. Here we combine projection-specific electrophysiological and rabies-mediated input mapping in mice to uncover adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are highly functionally integrated into local excitatory circuitry and have heightened activity compared to adulthood. Chemogenetic suppression of top-down neuron activity selectively during adolescence, but not later periods, produces long-lasting visual attentional behavior deficits, and results in excessive loss of local excitatory inputs in adulthood. Our study reveals an adolescent sensitive period when top-down neurons integrate local circuits with long-range connectivity to produce attentional behavior.

The brain of the African wild dog. IV. The visual system.

Abstract: The variegated pelage and social complexity of the African wild dog (Lycaon pictus) hint at the possibility of specializations of the visual system. Here, using a range of architectural and immunohistochemical stains, we describe the systems-level organization of the image-forming, nonimage forming, oculomotor, and accessory optic, vision-associated systems in the brain of one representative individual of the African wild dog. For all of these systems, the organization, in terms of location, parcellation and topology (internal and external), is very similar to that reported in other carnivores. The image-forming visual system consists of the superior colliculus, visual dorsal thalamus (dorsal lateral geniculate nucleus, pulvinar and lateral posterior nucleus) and visual cortex (occipital, parietal, suprasylvian, temporal and splenial visual regions). The nonimage forming visual system comprises the suprachiasmatic nucleus, ventral lateral geniculate nucleus, pretectal nuclear complex and the Edinger-Westphal nucleus. The oculomotor system incorporates the oculomotor, trochlear and abducens cranial nerve nuclei as well as the parabigeminal nucleus, while the accessory optic system includes the dorsal, lateral and medial terminal nuclei. The extent of similarity to other carnivores in the systems-level organization of these systems indicates that the manner in which these systems process visual information is likely to be consistent with that found, for example, in the well-studied domestic cat. It would appear that the sociality of the African wild dog is dependent upon the processing of information extracted from the visual system in the higher-order cognitive and affective neural systems.

Amplification of potential thermogenetic mechanisms in cetacean brains

Abstract: To elucidate causality underlying the evolution of large brains in cetaceans, we examined the brains of 16 cetartiodactyl species for evidence of non-shivering thermogenesis. In comparison to the artiodactyl brain, the cetacean brain exhibits an expanded expression of uncoupling protein 1 (UCP1, UCPs being mitochondrial inner membrane proteins that dissipate the proton gradient to generate heat) in cortical neurons, localization of UCP4 within a substantial proportion of glia throughout the brain, and an increased density of noradrenergic axonal boutons (noradrenaline functioning to control concentrations of and activate UCPs). Thus, cetacean brains possess multiple characteristics indicative of intensified thermogenetic functionality that can be related to their current and historical obligatory aquatic niche. These findings necessitate reassessment of our concepts regarding the reasons for large brain evolution and associated functional capacities in cetaceans.

Comparative neocortical neuromorphology in felids: African lion, African leopard, and cheetah

Abstract: The present study examines cortical neuronal morphology in the African lion (Panthera leo leo), African leopard (Panthera pardus pardus), and cheetah (Acinonyx jubatus jubatus). Tissue samples were removed from prefrontal, primary motor, and primary visual cortices and investigated with a Golgi stain and computer-assisted morphometry to provide somatodendritic measures of 652 neurons. Although neurons in the African lion were insufficiently impregnated for accurate quantitative dendritic measurements, descriptions of neuronal morphologies were still possible. Qualitatively, the range of spiny and aspiny neurons across the three species was similar to those observed in other felids, with typical pyramidal neurons being the most prominent neuronal type. Quantitatively, somatodendritic measures of typical pyramidal neurons in the cheetah were generally larger than in the African leopard, despite similar brain sizes. A MARsplines analysis of dendritic measures correctly differentiated 87.4% of complete typical pyramidal neurons between the African leopard and cheetah. In addition, unbiased stereology was used to compare the soma size of typical pyramidal neurons (n = 2,238) across all three cortical regions and gigantopyramidal neurons (n = 1,189) in primary motor and primary visual cortices. Both morphological and stereological analyses indicated that primary motor gigantopyramidal neurons were exceptionally large across all three felids compared to other carnivores, possibly due to specializations related to the felid musculoskeletal systems. The large size of these neurons in the cheetah which, unlike lions and leopards, does not belong to the Panthera genus, suggests that exceptionally enlarged primary motor gigantopyramidal neurons evolved independently in these felid species.

Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1.

Abstract: Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene. Neuroanatomical alterations have been reported in both male and female individuals with FXS, yet the morphological underpinnings of these alterations have not been elucidated. In the current study, we found structural changes in both male and female rats that model FXS, some of which are similarly impaired in both sexes, including the superior colliculus and periaqueductal gray, and others that show sex-specific changes. The splenium of the corpus callosum, for example, was only impaired in males. We also found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Furthermore, we found that overall, male rats have higher brain-wide diffusion than female rats. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and reveal an impairment at the level of the axon that could cause structural changes in white matter regions.

Evolution of regulatory signatures in primate cortical neurons at cell type resolution

Abstract: The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell type-specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype-specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder and drug addiction. We observe preferential evolutionary divergence in neuron-subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergo subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type-dependent gene expression programs, and provides a resource for further exploration of human brain evolution and function. SIGNIFICANCE The cerebral cortex of the human brain is a highly complex, heterogeneous tissue that contains many cell types which are exquisitely regulated at the level of gene expression by non-coding regulatory elements, presumably, in a cell-type-dependent manner. However, assessing the regulatory elements in individual cell types is technically challenging, and therefore, most of the previous studies on gene regulation were performed with bulk brain tissue. Here we analyze two major types of neurons isolated from the cerebral cortex of humans, chimpanzees and rhesus macaques, and report complex patterns of cell-type-specific evolution of the regulatory elements in numerous genes. Many genes with evolving regulation are implicated in language abilities as well as psychiatric disorders.