Past events

It is clear that much of the masculinization of the brain in rats and mice is mediated by aromatized metabolites of testicular androgens acting upon estrogen receptors (ERs). For example, exogenous estrogens, which presumably exert little effect on androgen receptors (ARs), can reverse the loss of masculine behavior and neural morphology in males that have been castrated, both in development and adulthood. However, we find that rats and mice carrying a dysfunctional AR gene, so-called testicular feminization mutation (Tfm) males, are partly or completely demasculinized in terms of at least one non-reproductive behavior and each of the numerous brain regions we have examined so far. These findings indicate that in fact AR normally plays a role in the masculinization of at least some behaviors, and potentially every brain region, in rodents. For example, the medial amygdala (MeA) is about 150% larger in volume in wildtype (wt) male rats than in wt females. Tfm males display an intermediate volume, significantly greater than wt females yet significantly less than wt males. Astrocytes in the posterodorsal portion of the MeA (MePD) of rats are also sexually dimorphic, both in number and arbor complexity, and Tfm males are wholly feminine in these features. Likewise, in our measurements of sexually dimorphic characters in the ventromedial hypothalamus (VMH), the suprachiasmatic nucleus (SCN), and the paraventricular nucleus (PVN), Tfm males are wholly feminine. Even in the sexually dimorphic nucleus of the preoptic area (SDNPOA), where the volume is masculine in Tfm males, the size of the neurons is nevertheless reduced in Tfm males compared to wt males. It is difficult to assess masculine reproductive behavior in Tfm males because they have an entirely feminine exterior phenotype, with a clitoris, vagina, etc. Nevertheless, they have been reported to show many masculine reproductive behaviors, as would be expected if those were mediated by ERs. However, we find that anxiety-related behaviors, such as measured in an open field with a novel object, the elevated plus maze, and the light/dark box, are greater in Tfm males than in wt males in both rats and mice. Tfm animals also show a heightened corticosterone response to mild stress. These results suggest that masculinization of anxiety-related behavior is heavily reliant on stimulation of AR, presumably in the brain. We are exploring the sites of AR action by use of Cre- lox technology to delete AR in selective tissues. We are using the same technology to explore the site(s) of androgen action on the spinal nucleus of the bulbocavernosus (SNB), a group of motoneurons that innervate two striated muscles, the bulbocavernosus and levator ani (BC/LA), which are attached to the base of the penis. By selectively deleting AR in either motoneurons alone, or in muscle fibers alone, we hope to understand how androgen spares this system from apoptosis in development, and regulates neural plasticity of the motoneurons in adulthood.

Thousands of new neurons are generated daily during adult life but only a fraction of them survive, mature and incorporate into the neural circuits; the rest die, and their corpses are presumably cleared by other healthy cells. How the dying neurons are removed and how such clearance influences neurogenesis are not well understood. We identified an unexpected phagocytic role for the doublecortin (DCX)-positive neuronal progenitor cells during adult neurogenesis. Our in vivo and ex vivo studies demonstrate that DCX+ cells comprise of a significant phagocytic population within the neurogenic zones. Intracellular engulfment protein ELMO1, which promotes Rac activation downstream of phagocytic receptors, was required for phagocytosis by DCX+ cells. Disruption of engulfment in vivo genetically (in Elmo1-null mice) or pharmacologically (in wild type mice) led to reduced uptake by DCX+ cells, accumulation of apoptotic nuclei in the neurogenic niches, and impaired neurogenesis. Implication of this phenomenon could be relevant to clinical conditions associated with induced (stroke) or impaired (depression) neurogenesis. We extended our studies of phagocytic activity to neurodevelopmental diseases, such as autistic spectrum disorders and Rett syndrome, in particular. We found that myeloid compartment of Rett mice is impaired in phagocytic activity. When myeloid compartment is replaced using bone marrow transplantation from wild-type bone marrow into Mecp2‒/y mice, the disease is arrested and life expectancy is increased by more than five-fold. Bone marrow transplantation results in engraftment of the brain parenchyma with wild type microglia-like cells, capable of clearing apoptotic debris load, which presumably allows more efficient neuronal function. Our data unexpectedly implicate myeloid cells in Rett pathology, and suggest that these immune cells might offer a feasible target for future therapeutic intervention for this devastating disease.

A multitude of experiments over the past century have yielded deep insights into the cellular and synaptic organization of the microcircuitry of the neocortex and its possible role as a functional unit - a column of cells across 6 layers. The available data is, however, not standardized, is highly fragmented and often conflicting. More importantly, there are large gaps in our knowledge requiring an impractical number of experiments to fill. We therefore developed a strategy to accelerate a comprehensive analysis of the neocortical column by attempting to reconstruct it from partial information. We performed a spectrum of standardized biological experiments on strategic cellular and synaptic properties of the microcircuitry of the somatosensory cortex of a young rat and gathered further relevant data from previously published studies. We developed a generic supercomputer-based platform to build and simulate biologically-detailed brain models, and attempted to reconstruct a first draft of a unifying model at the cellular level of detail. The model integrates and unifies most of the current data, significantly predicts missing data, and provides a broad range of new insights into the structural and functional organization of neocortical microcircuitry. The model also serves as a virtual specimen for a new generation of simulation-based experimentation that can accelerate an integrated understanding of the cellular and synaptic basis of neocortical function.

Cognition materializes in an interpersonal space. The emergence of complex behaviors requires the coordination of actions among individuals according to a shared set of rules. Despite the central role of other individuals in shaping our minds, experiments typically isolate human or animal subjects from their natural environment by placing them in a sealed quiet room where interactions occur solely with a computer screen. In everyday life, however, we spend most of our time interacting with other individuals. In the talk I will argue in favor of a shift from a single-brain to a multi-brain frame of reference. I will present a series of studies aimed at characterizing the brain-to-brain coupling during real life social interaction. The data suggest that in many cases the neural processes in one brain are coupled to the neural processes in another brain via the transmission of a signal through the environment. The brain-to-brain neural coupling exposes a shared neural substrate that exhibits temporally aligned response patterns across communicators. The recording of the neural responses from two brains opens a new window into the neural basis of interpersonal communication, and may be used to assess verbal and non-verbal forms of interaction in both human and other model systems.

Any physical device, including computers, when comparing A to B, must send the information to point C. Explanations of brain processing take such a convergence for granted thus generating models relying on increasingly converging hierarchical streams. Such models, however, consistently fail to explain many perceptual phenomena. To see whether the brain, at times, can compare (integrate, process) events that take place at different loci without sending the information to a common target, I performed experiments in three modalities, somato-sensory, auditory, and visual, where 2 different loci at the primary cortex were stimulated. Subjects were able to integrate inputs in time and space affecting small separate cortical loci. The ability to correlate activity between loci was independent of cortical distance up to 2-4 cm. Given the organization of sensory cortex where localized responses in primary cortex do not interact while convergence in downstream areas results in loss of individual stimulus identity and in decreasing selectivity to elementary stimuli, those results cannot be explained by conventional convergence models. We must thus assume a non-converging mechanism whereby two (or more) activated cortical loci can be integrated without sending information via axons into another downstream integrating site. Once we allow for such a non-converging mechanism, many perceptual phenomena can be viewed differently. Object recognition and representation is such a phenomenon that, I suggest, does not result from hierarchical convergence of cells with ever-increasing feature selectivity but rather from parallel interactions between various visual and non-visual areas. If my hypothesis of the brain ability to relate activity taking place at separate loci without using convergence-by-wires is correct, it implies that the brain can use heretofore unconsidered (unknown?) parallel processing and that conventional models, including computer programs, would not be able to capture many brain processes.

The neuronal mechanisms underlying perceptual grouping of discrete, similarly oriented elements are not well understood. To investigate this, we imaged population responses in V1 of monkeys trained on a contour detection task. Mapping neuronal populations processing contour/background elements in V1 enabled studying the role of two encoding mechanisms: strength of population response and synchronization. Response maps early in time showed activation patches corresponding to the contour/background individual elements. An early increased synchronization between the contour elements, accompanied by decreased synchronization between the background elements, suggested that contour integration is initiated with synchronization changes. However only response modulation at later times, defined by increased activity in the contour elements, along with suppressed activity in the background elements, enabled to visualize in single trials, a salient continuous contour segregated from a noisy background. Finally, the late modulation was correlated with psychophysical performance of contour saliency, further supporting its role in contour perception. In the second part of this talk we will demonstrate the effects of microsaccades on perceptual mechanisms in V1.