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ABSTRACT The nucleus accumbens (NAcc) and ventral pallidum (VP) are key nodes in the mesolimbic reward pathway that facilitate stimulus salience, including the regulation of social motivation and attachment. Primate species display variation in social behaviors, including different levels of impulsivity, bonding, and aggression. Previous research has implicated neuromodulation of the reward pathway in the differential expression of various social behaviors, suggesting that differences in neurotransmitter innervation may play a role in species‐specific patterns. To explore this, we examined serotonergic innervation in the NAcc and VP among primates. We used stereology to quantify serotonin transporter‐immunoreactive (SERT‐ir) axon length density in the NAcc and VP of 13 primate species, including humans, great apes, and cercopithecid and platyrrhine monkeys. Our data show that serotonergic innervation density within both the NAcc and VP is highly conserved among species. This finding contrasts with our previous findings of higher levels of SERT‐ir axons in the dorsal striatum of humans and great apes relative to monkeys, a human‐specific increase in dopaminergic innervation within the NAcc and VP, and a human‐specific increase of neuropeptide Y in the NAcc, highlighting the mosaic nature of innervation patterns among species. 

ABSTRACT The cerebral cortex accounts for substantial energy expenditure, primarily driven by the metabolic demands of synaptic signaling. Mitochondria, the organelles responsible for generating cellular energy, play a crucial role in this process. We investigated ultrastructural characteristics of the primary visual cortex in 18 phylogenetically diverse mammals, spanning a broad range of brain sizes from mouse to elephant. Our findings reveal remarkable uniformity in synapse density, postsynaptic density (PSD) length, and mitochondria density, indicating functional and metabolic constraints that maintain these fundamental features. Notably, we observed an average of 1.9 mitochondria per synapse across mammalian species. When considered together with the trend of decreasing neuron density with larger brain size, we find that brain enlargement in mammals is characterized by increasing proportions of synapses and mitochondria per cortical neuron. These results shed light on the adaptive mechanisms and metabolic dynamics that govern cortical ultrastructure across mammals. 

ABSTRACT Alzheimer's disease (AD) and its associated pathology have been primarily identified in humans, who have relatively large brains and long lifespans. To expand what is known about aging and neurodegeneration across mammalian species, we characterized amyloid‐beta (Aβ) and tau lesions in five species of aged felids (n= 9; cheetah, clouded leopard, African lion, serval, Siberian tiger). We performed immunohistochemistry to detect Aβ40 and Aβ42 in plaques and vessels and hyperphosphorylated tau in the temporal lobe gyrus sylvius and in the CA1 and CA3 subfields of the hippocampus. We also quantified the densities and morphological types of microglia expressing IBA1. We found that diffuse Aβ42 plaques, but not dense‐core plaques, were present more frequently in the temporal cortex and tended to be more common than Aβ40 plaques across species. Conversely, vascular Aβ was labeled more consistently with Aβ40 for each species on average. Although all individuals showed some degree of Aβ40 and/or Aβ42 immunoreactivity, only the cheetahs and clouded leopards exhibited intraneuronal hyperphosphorylated tau (i.e., pretangles), which was more common in the hippocampus. Reactive, intermediate microglia were significantly associated with total Aβ40 vessel area and pretangle load in the hippocampus. This study demonstrates the co‐occurrence of Aβ and tau pathology in two felid species, cheetahs and clouded leopards. Overall, these results provide an initial view of the manifestation of Aβ and tau pathology in aged, large‐brained felids, which can be compared with markers of neurodegeneration across different taxa, including domestic cats, nonhuman primates, and humans. 

Abstract Human newborns are considered altricial compared with other primates because they are relatively underdeveloped at birth. However, in a broader comparative context, other mammals are more altricial than humans. It has been proposed that altricial development evolved secondarily in humans due to obstetrical or metabolic constraints, and in association with increased brain plasticity. To explore this association, we used comparative data from 140 placental mammals to measure how altriciality evolved in humans and other species. We also estimated how changes in brain size and gestation length influenced the timing of neurodevelopment during hominin evolution. Based on our data, humans show the highest evolutionary rate to become more altricial (measured as the proportion of adult brain size at birth) across all placental mammals, but this results primarily from the pronounced postnatal enlargement of brain size rather than neonatal changes. In addition, we show that only a small number of neurodevelopmental events were shifted to the postnatal period during hominin evolution, and that they were primarily related to the myelination of certain brain pathways. These results indicate that the perception of human altriciality is mostly driven by postnatal changes, and they point to a possible association between the timing of myelination and human neuroplasticity. 

Abstract Neuronal plasticity can vary remarkably in its form and degree across animal species. Adult neurogenesis, namely the capacity to produce new neurons from neural stem cells through adulthood, appears widespread in non-mammalian vertebrates, whereas it is reduced in mammals. A growing body of comparative studies also report variation in the occurrence and activity of neural stem cell niches between mammals, with a general trend of reduction from small-brained to large-brained species. Conversely, recent studies have shown that large-brained mammals host large amounts of neurons expressing typical markers of neurogenesis in the absence of cell division. In layer II of the cerebral cortex, populations of prenatally generated, non-dividing neurons continue to express molecules indicative of immaturity throughout life (cortical immature neurons; cINs). After remaining in a dormant state for a very long time, these cINs retain the potential of differentiating into mature neurons that integrate within the preexisting neural circuits. They are restricted to the paleocortex in small-brained rodents, while extending into the widely expanded neocortex of highly gyrencephalic, large-brained species. The current hypothesis is that these populations of non-newly generated “immature” neurons might represent a reservoir of developmentally plastic cells for mammalian species that are characterized by reduced stem cell-driven adult neurogenesis. This indicates that there may be a trade-off between various forms of plasticity that coexist during brain evolution. This balance may be necessary to maintain a “reservoir of plasticity” in brain regions that have distinct roles in species-specific socioecological adaptations, such as the neocortex and olfactory structures. 

Abstract Astrocytes are the main homeostatic cell of the brain involved in many processes related to cognition, immune response, and energy expenditure. It has been suggested that the distribution of astrocytes is associated with brain size, and that they are specialized in humans. To evaluate these, we quantified astrocyte density, soma volume, and total glia density in layer I and white matter in Brodmann's area 9 of humans, chimpanzees, baboons, and macaques. We found that layer I astrocyte density, soma volume, and ratio of astrocytes to total glia cells were highest in humans and increased with brain size. Overall glia density in layer I and white matter were relatively invariant across brain sizes, potentially due to their important metabolic functions on a per volume basis. We also quantified two transporters involved in metabolism through the astrocyte‐neuron lactate shuttle, excitatory amino acid transporter 2 (EAAT2) and glucose transporter 1 (GLUT1). We expected these transporters would be increased in human brains due to their high rate of metabolic consumption and associated gene activity. While humans have higher EAAT2 cell density, GLUT1 vessel volume, and GLUT1 area fraction compared to baboons and chimpanzees, they did not differ from macaques. Therefore, EAAT2 and GLUT1 are not related to increased energetic demands of the human brain. Taken together, these data provide evidence that astrocytes play a unique role in both brain expansion and evolution among primates, with an emphasis on layer I astrocytes having a potentially significant role in human‐specific metabolic processing and cognition. 

Structural changes involving new neurons can occur through stem cell-driven neurogenesis, and through incorporation of late-maturing “immature” neurons into networks, namely undifferentiated neuronal precursors frozen in a state of arrested maturation. The latter have been found in the cerebral cortex and are particularly abundant in large-brained mammals, covarying with the size of the brain and cortex. Similar cells have been described in the amygdala of some species, although their features and interspecies variation remain poorly understood. Here, their occurrence, number, morphology, molecular expression, age-related changes, and anatomical distribution in amygdala subdivisions were systematically analyzed in eight diverse mammalian species (including mouse, naked mole rat, rabbit, marmoset, cat, sheep, horse, and chimpanzee) widely differing in neuroanatomy, brain size, life span, and socioecology. We identify converging evidence that these amygdala cells are immature neurons and show marked phylogenetic variation, with a significantly greater prevalence in primates. The immature cells are largely located within the amygdala’s basolateral complex, a region that has expanded in primate brain evolution in conjunction with cortical projections. In addition, amygdala immature neurons also appear to stabilize in number through adulthood and old age, unlike other forms of plasticity that undergo marked age-related reduction. These results support the emerging view that large brains performing complex socio-cognitive functions rely on wide reservoirs of immature neurons. 

The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.