Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS), which has been suggested to enhance cognitive functions through GABAA receptor signaling by its metabolites. It has been shown that the level of pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances pregnenolone in the CNS in rats, suggesting that pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO). DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI) deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.

What are the rules relating the size of the brain and its structures to the number of cells that compose them and their average sizes? We have shown previously that the cerebral cortex, cerebellum and the remaining brain structures increase in size as a linear function of their numbers of neurons and non-neuronal cells across 6 species of primates. Here we describe that the cellular composition of the same brain structures of 5 other primate species, as well as humans, conform to the scaling rules identified previously, and that the updated power functions for the extended sample are similar to those determined earlier. Accounting for phylogenetic relatedness in the combined dataset does not affect the scaling slopes that apply to the cerebral cortex and cerebellum, but alters the slope for the remaining brain structures to a value that is similar to that observed in rodents, which raises the possibility that the neuronal scaling rules for these structures are shared among rodents and primates. The conformity of the new set of primate species to the previous rules strongly suggests that the cellular scaling rules we have identified apply to primates in general, including humans, and not only to particular subgroups of primate species. In contrast, the allometric rules relating body and brain size are highly sensitive to the particular species sampled, suggesting that brain size is neither determined by body size nor together with it, but is rather only loosely correlated with body size.

In the present study, galago brains were sectioned in the coronal, sagittal or horizontal planes, and sections were processed with several different histochemical and immunohistochemical procedures to reveal the architectonic characteristics of the various cortical areas. The histochemical methods used included the traditional Nissl, cytochrome oxidase and myelin stains, as well as a zinc stain, which reveals free ionic zinc in the axon terminals of neurons. Immunohistochemical methods include parvalbumin (PV) and calbindin (CB), both calcium-binding proteins, and the vesicle glutamate transporter 2 (VGluT2). These different procedures revealed similar boundaries between areas, which suggests that functionally relevant borders were being detected. These results allowed a more precise demarcation of previously identified areas. As thalamocortical terminations lack free ionic zinc, primary cortical areas were most clearly revealed by the zinc stain, due to the poor zinc staining of layer 4. Area 17 was especially prominent, as the broad layer 4 was nearly free of zinc stain. However, this feature was less pronounced in the primary auditory and somatosensory cortex. As VGluT2 is expressed in thalamocortical terminations, layer 4 of primary sensory areas was darkly stained for VGluT2. Primary motor cortex had reduced VGluT2 staining, and increased zinc-enriched terminations in the poorly developed granular layer 4 compared to the adjacent primary somatosensory area. The middle temporal visual (MT) showed increased PV and VGluT2 staining compared to the surrounding cortical areas. The resulting architectonic maps of cortical areas in galagos can usefully guide future studies of cortical organizations and functions.

Squirrels are highly visual mammals with an expanded cortical visual system and a number of well-differentiated architectonic fields. In order to describe and delimit cortical fields, subdivisions of cortex were reconstructed from serial brain sections cut in the coronal, sagittal, or horizontal planes. Architectonic characteristics of cortical areas were visualized after brain sections were processed with immunohistochemical and histochemical procedures for revealing parvalbumin, calbindin, neurofilament protein, vesicle glutamate transporter 2, limbic-associated membrane protein, synaptic zinc, cytochrome oxidase, myelin or Nissl substance. In general, these different procedures revealed similar boundaries between areas, suggesting that functionally relevant borders were being detected. The results allowed a more precise demarcation of previously identified areas as well as the identification of areas that had not been previously described. Primary sensory cortical areas characterized by sparse zinc staining of layer 4, as thalamocortical terminations lack zinc, as well as by layer 4 terminations rich in parvalbumin and vesicle glutamate transporter 2. Primary areas also expressed higher levels of cytochrome oxidase and myelin. Primary motor cortex was associated with large SMI-32 labeled pyramidal cells in layers 3 and 5. Our proposed organization of cortex in grey squirrels includes both similarities and differences to the proposed of cortex in other rodents such as mice and rats. The presence of a number of well-differentiated cortical areas in squirrels may serve as a guide to the identification of homologous fields in other rodents, as well as a useful guide in further studies of cortical organization and function.

Tree shrews are small mammals that bear some semblance to squirrels, but are actually close relatives of primates. Thus, they have been extensively studied as a model for the early stages of primate evolution. In the present study, subdivisions of cortex were reconstructed from brain sections cut in the coronal, sagittal or horizontal planes, and processed for parvalbumin (PV), SMI-32 immunopositive neurofilament protein epitopes, vesicle glutamate transporter 2 (VGluT2), free ionic zinc, myelin, cytochrome oxidase (CO) and Nissl substance. These different procedures revealed similar boundaries between areas, suggesting the detection of functionally relevant borders and allowed a more precise demarcation of cortical areal boundaries. Primary cortical areas were most clearly revealed by the zinc stain, due to the poor staining of layer 4, as thalamocortical terminations lack free ionic zinc. Area 17 (V1) was especially prominent, as the broad layer 4 was nearly free of zinc stain. However, this feature was less pronounced in primary auditory and somatosensory, cortex. In primary sensory areas, thalamocortical terminations in layer 4 densely express VGluT2. Auditory cortex consists of two architectonically distinct subdivisions, a primary core region (Ac), surrounded by a belt region (Ab) that had a slightly less developed koniocellular appearance. Primary motor cortex (M1) was identified by the absence of VGluT2 staining in the poorly developed granular layer 4 and the presence of SMI-32 labeled pyramidal cells in layers 3 and 5. The presence of well-differentiated cortical areas in tree shrews indicates their usefulness in studies of cortical organization and function.

The temporal cortex of grey squirrels contains three architectonically distinct regions. One of these regions, the temporal anterior (Ta) region has been identified in previous physiological and anatomical studies as containing several areas that are largely auditory in function. Consistent with this evidence, Ta has architectonic features that are internally somewhat variable, but overall sensory in nature. In contrast, the caudally adjoining temporal intermediate region (Ti) has architectonic features that suggest higher order and possibly multisensory processing. Finally, the most caudal region, composed of previously defined temporal medial (Tm) and temporal posterior (Tp) fields, again has more of the appearance of sensory cortex. To better understand their functional roles, we injected anatomical tracers into these regions to reveal their thalamic connections. As expected, the dorsal portion of Ta, containing two primary or primary-like auditory areas, received inputs from the ventral and magnocellular divisions of the auditory medial geniculate complex, MGv and MGm. The most caudal region, Tm plus Tp, received inputs from the large visual pulvinar of squirrels, possibly accounting for the sensory architectonic characteristics of this region. However, Tp additionally receives inputs from the magnocellular (MGm) and dorsal (MGd) divisions of the medial geniculate complex, implicating Tp in bisensory processing. Finally, the middle region, Ti, had auditory inputs from MGd and MGm, but not from the visual pulvinar, providing evidence that Ti has higher-order auditory functions. The results indicate that the architectonically distinct regions of temporal cortex of squirrels are also functionally distinct. Understanding how temporal cortex is functionally organized in squirrels can guide interpretations of temporal cortex organization in other rodents where architectonic subdivisions are not as obvious.