g-Aminobutyric acid (GABA)ergic inputs are strategically positioned to gate synaptic integration along the dendritic arbor of pyramidal cells. However, their spatiotemporal dynamics during behavior are poorly understood. Using an optical-tagging electrophysiological approach to record and label somatostatin-expressing (Sst) interneurons (GABAergic neurons specialized for dendritic inhibition), we discovered a layer-specific modulation of their activity in behaving mice. Sst interneuron subtypes, residing in different cortical layers and innervating complementary laminar domains, exhibited opposite activity changes during transitions to active wakefulness. The relative weight of vasoactive intestinal peptide-expressing (Vip) interneuron-mediated inhibition of distinct Sst interneurons and cholinergic modulation determined their in vivo activity. These results reveal a state-dependent laminar influence of Sst interneuronmediated inhibition, with implications for the compartmentalized regulation of dendritic signaling in the mammalian neocortex.

Cholinergic actions are critical for normal cortical cognitive functions. The release of acetylcholine (ACh) in neocortex and the impact of this neuromodulator on cortical computations exhibit remarkable spatiotemporal precision, as required for the regulation of behavioral processes underlying attention and learning. We discuss how the organization of the cholinergic projections to the cortex and their release properties might contribute to this specificity. We also review recent studies suggesting that the modulatory influences of ACh on the properties of cortical neurons can have the necessary temporal dynamic range, emphasizing evidence of powerful interneuron subtype-specific effects. We discuss areas that require further investigation and point to technical advances in molecular and genetic manipulations that promise to make headway in understanding the neural bases of cholinergic modulation of cortical cognitive operations.

Real per capita GDP growth is relatively flat in the United States. Rising surgical health care expenditures and national health care expenditures are a significant issue for the US population. Unfortunately, programs at the state and federal level as well as private programs, for the last 50 years have not been able to slow the growth in health care expenditures. These trends are likely to continue and the effects will be: * A change in the US standard of living as surgical and health care expenditures become a larger part of the earned dollar per American especially with the current volatility of the US economy, * A rise in the cost of products made in the United States to pay the rising health care bill with a concomitant change in our national and international standard of living, and * An increasing debt and increases in federal and state taxes which will be required to maintain the current health care system, ie, Medicare, Medicaid, and the private health care insurance payment scheme, which has not changed substantially over the past 40 to 50 years. Surgeons must look at the incremental benefit of new technologies and procedures and determine which to choose if we are to slow the growth of surgical health care expenditures.

Summary Brain networks contain a large diversity of functionally distinct neuronal elements, each with unique properties, enabling computational capacities and supporting brain functions. Understanding their functional implications for behavior requires the precise identification of the cell types of a network and in vivo monitoring of their activity profiles. Here, we developed a channelrhodopsin-assisted patching method allowing the efficient in vivo targeted recording of neurons identified by their molecular, electrophysiological and morphological features. The method has a high yield, does not require visual guidance, and thus can be applied at any depth in the brain. This approach overcomes limitations of present technologies. We validate this strategy by in vivo recordings of identified subtypes of GABAergic and glutamatergic neurons in deep cortical layers, subcortical cholinergic neurons and neurons in the thalamic reticular nucleus in anesthetized and awake mice. We propose this method as an important complement to existing technologies to relate specific cell type activity to brain circuitry, function and behavior.

The basal forebrain cholinergic system projects broadly throughout the cortex and constitutes a critical source of neuromodulation for arousal and attention. Traditionally, this system was thought to function diffusely. However, recent studies have revealed a high degree of spatiotemporal specificity in cholinergic signaling. How the organization of cholinergic afferents confers this level of precision remains unknown. Here, using intersectional genetic fate mapping, we demonstrate that cholinergic fibers within the cortex exhibit remarkable laminar and regional specificity and that this is organized in accordance with cellular birthdate. Strikingly, birthdated cholinergic projections within the cortex follow an inside-out pattern of innervation. While early born cholinergic populations target deep layers, late born ones innervate superficial laminae. We also find that birthdate predicts cholinergic innervation patterns within the amygdala, hippocampus, and prefrontal cortex. Our work reveals previously unappreciated specificity within the cholinergic system and the developmental logic by which these circuits are assembled.