The brain is the most complex object of study for humankind. This organ comprises about 100 billion nerve cells consisting of thousands of distinct cell types based on morphology, chemistry, and physiology.

Each of these cells may make thousands of connections, or synapses, with adjoining and even distant cells. Overall, there are likely to be more than 100 trillion synapses in the human brain. Communication across these synapses is accomplished by more than a hundred different chemicals, and each of these chemical neurotransmitters may have multiple receptor types with which it can interact at the receiving end.

A final measure of the brain's complexity is its dynamic nature; it changes constantly, undergoing significant structural modification in its synaptic architecture in response to environmental stimuli. Were it not for this "plasticity" of the brain, we could not learn, we could not adapt, we could not change. Since the abnormal function of the brain is the substrate of mental illness, neuroscience is of central importance to psychiatry.

In a previous article, I described "bottom-up" tools provided by molecular genetics to investigate brain function and disease. In this article I will describe exciting "top-down" approaches that are giving us a more integrated view of how the brain works.

Neurons in the brain are organized into functionally specific parallel circuits. Such circuits underlie the processing of sensory inputs and motor outputs. They also underlie the processing of cognition and emotion.

By combining research using animal models and modern neuroimaging tools, such as functional magnetic resonance imaging and positron emission tomography, it is possible to investigate the specific circuits involved in the processing of normal cognition or emotion. This information should be a critical stepping stone to identifying specific malfunctions that cause mental disorders. The gains to be realized from bringing basic science such as integrative neurobiology and cognitive neuroscience together with clinical investigation has prompted the National Institute of Mental Health to organize new programs in translational biology. These will accelerate the application of basic work performed in animals and normal human subjects-and even cellular or molecular models-to the clinical research arena.

One specific example of such a translation is our emerging understanding of the neurobiology of fear and its possible application to understanding anxiety disorders. Using simple rodent models, several investigators have isolated critical pathways in the brain involved in the processing of fear. These pathways involve the flow of information from the cerebral cortex and thalamus to the amygdala, a nucleus within the temporal lobes. The amygdala is a complex structure; its outputs have been traced to regions of the hypothalamus that control the fight-or-flight response via the sympathetic nervous system, as well as to the region that integrates stress signals and ultimately controls the release of cortisol. In addition, the amygdala has outputs to multiple other brain regions that govern the perception of pain, alter levels of arousal and attention, and initiate emergency motor responses. The amygdala also is involved in initiating the recording of emotional memories and associated cognitive memories that permit an organism to predict future danger and, therefore, to behave adaptively.

The identification of these circuits in animals has permitted basic researchers who work with human subjects to attempt to activate fear pathways, with such stimuli as fearful faces or aversive visual scenes, while subjects are undergoing neuroimaging examinations. There is now evidence that the human amygdala appears to play a similarly critical role in processing fearful stimuli and in initiating the first stages of the formation of emotional memories. Much more basic research needs to be done in animals, including mapping the connections within the amygdala and understanding the precise mechanisms by which emotional memories are recorded. In addition, more studies are required in normal human subjects to solidify our knowledge of how danger is appraised and fear is represented in the human brain. The implications for psychiatry are enormous.

As research on fear circuitry progresses, we will be able to address issues such as whether posttraumatic stress disorder or other anxiety disorders reflect abnormal function somewhere within this circuit. We can address the ways in which neural representation of traumatic memories differs from adaptive memories of less overwhelming dangers. We can begin to ask whether panic attacks utilize some of the same circuitry and how panic disorder can progress to agoraphobia.

The opportunity to examine specific brain pathways, observe the malfunction in mental illness, and then observe the effects of treatment represents an exciting series of advances for psychiatric research. No longer are we constrained to searching for crude peripheral biological markers such as platelet serotonin receptors. With new tools and paradigms, we can move beyond our prior need to make enormous inferential leaps from peripheral neuroendocrine challenge responses to the brain. Being able to examine the function and dysfunction of the living, thinking, feeling human brain directly and to develop incisive hypotheses about brain function and dysfunction based on the explosion of knowledge provided by basic neuroscience makes these truly exciting times in psychiatric research.