Past events

Fear is a crucial adaptive component of the behavioral repertoire that is generated in relation to stimuli which threaten to perturb homeostasis. Fear-relevant associations are learned and consolidated as part of long term memory. After learning, fear responses are modulated through processes termed safety learning and extinction. Perturbation of these mechanisms can lead to disproportional anxiety states and anxiety disorders. Recent years have seen considerable progress in identifying relevant brain areas – such as the amygdala, the hippocampus and the prefrontal cortex - and neurophysiological principles. Key mechanisms, involving rhythmic oscillations of neuronal subpopulations and neuromodulatory influences, will be discussed

Understanding the neural mechanisms of visual object recognition is a difficult task in part, because for any given object it is not clear, which exact part of the brain to study. Yet evolution has presented us with a unique model system to decipher these mechanisms. The temporal lobes of macaque monkeys contain neural machinery to support face recognition consisting of six discrete patches of face-selective cortex. The two main organizing features of this system – concentration of cells encoding the same complex object category into modules and spatial separation of modules – make it possible to break down the process of face recognition into its components. In my talk I will present anatomical results supporting the notion that the distributed face patches really are part of an integrated face-processing machine, and electrophysiological results showing that each patch subserves a distinct computational function. In the second part of my talk I will turn to something completely different, attention. Using fMRI in macaque monkeys, we found a network of areas to be modulated by attention in motion-discrimination task, included a hitherto unsuspected region within inferotemporal cortex, PITd. We then targeted PITd for electrophysiological recordings and electrical microstimulation in different tasks to learn about its role in sensory information processing and spatial attention. I will discuss the somewhat radical conclusion we arrived at, namely that PITd may constitute a region for attentional control.

Some people adapt well in the aftermath of traumatic events and are quickly able to inhibit their fear responses to trauma-associated stimuli. Fear responses, however, persist for longer periods of time for others to the point where they reach a pathological state. Why are some people more resilient to trauma while others are not? What are the neural substrates that underlie fear inhibition and extinction? Are these circuits deficient in patients with anxiety disorders? In my talk, I will focus on presenting translational data from the rat and human brains with the objective of trying to provide some preliminary answers to the above stated questions. Specifically, I will review human studies indicating that prefrontal areas homologous to those critical for extinction in rats. Furthermore, I will present some data to show that those brain regions in the rat brain appear to be structurally and functionally homologous to specific brain regions in the human brain. I will also show some data suggesting that these brain regions, the ventromedial prefrontal cortex (vmPFC) and the dorsal anterior cingulate cortex (dACC), appear to be deficient in patients with posttraumatic stress disorder (PTSD). I will present some structural and functional neuroimaging and psychophysiological studies done in our lab that focused on the neural mechanisms of fear extinction, particularly extinction recall and the contextual modulation of extinction recall. These recent studies suggest that: 1) human vmPFC is involved in the recall of extinction memory; 2) the size of the vmPFC might explain individual differences in the ability to modulate fear among humans; 3) hippocampal activation is observed during the recall of extinction memory in a context where extinction training took place but not in the initial conditioning context; 4) and the dACC may be involved in the expression of fear responses. I will also present recent neuroimaging and psychophysiological data from PTSD patients suggesting that 1) the retention of extinction memory is impaired in PTSD, and 2) the function of the vmPFC and dACC (measured by fMRI) appears to be impaired in PTSD in the context of fear extinction. Implications of these findings to the pathophysiology of anxiety disorders such as PTSD and current extinction-based behavioral therapies for anxiety disorders will be discussed.

17-β estradiol (E2) has been implicated to be neuroprotective, yet the mechanisms underlying E2-mediated protection against stroke remains unclear. The purpose of the current study was to elucidate the role of E2 in NADPH oxidase (NOX2) activation during ischemia/reperfusion induction of superoxide in the hippocampus CA1 region following global cerebral ischemia (GCI) and to explore the regulation of downstream proapoptotic factors by E2. Using a 4-vessel occlusion model to induce GCI, we showed that neuronal NOX2 localizes to the membrane and that NADPH oxidase activity and superoxide production were rapidly and markedly attenuated by E2 following reperfusion. Inhibition of NADPH oxidase activation via icv administration of a NOX2 competitive inhibitor, gp91ds-tat, strongly attenuated superoxide production and was neuroprotective. The increase of neuronal NADPH oxidase and superoxide following cerebral ischemia was shown to require Rac1 activation, as administration of a Rac1 inhibitor (NSC23766) significantly attenuated NADPH oxidase activation and superoxide production following stroke. NSC23766 treatment was also neuroprotective and improved spatial learning and memory. Interestingly, treatment with the competitive NOX2 inhibitor (Gp91ds-tat), but not the scrambled tat peptide control, attenuated acetylation of downstream p53 and reduced levels of the P53 transcriptional target and apoptotic factor, PUMA. Taken as a whole, our studies reveal a novel, membrane-mediated antioxidant mechanism of E2-induced neuroprotection via reduction of neuronal NOX2 activation, superoxide production and neuronal cell death in the hippocampus CA1 following cerebral ischemia.