Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations

Abstract

Cortical gamma band oscillations (GBO, 30–80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ∼40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia.

Gamma band directional interactions between basal forebrain and visual cortex during wake and sleep states

“…VC direction during WAKE and SWS states. Our observation of a robust gamma band Granger prediction from BF to VC is related to previous work showing that manipulations resulting in BF activation produce gamma oscillations in cortex (Bhattacharyya et al, 2013;Kim et al, 2015), which are thought to be mediated mainly by GABAergic BF corticopetal projections (Kim et al, 2015;Zant et al, 2016). Indeed, both cholinergic and particular classes of GABAergic neurons, termed ''W-max" and ''WP-max", are known to be activated during wakefulness (Hassani et al, 2009).…”

“…Recent findings have emphasized the importance of the GABAergic corticopetal system for initiating and sustaining EEG gamma oscillations. Accordingly, chemogenetic (Anaclet et al, 2015) or optogenetic (Kim et al, 2015) activation of GABAergic BF neurons has been shown to evoke robust cortical gamma oscillations, an effect that persists even when cholinergic BF neurons are destroyed using immunotoxic lesions (Kim et al, 2015). Indeed, previous studies demonstrating enhanced responsivity and sensitivity of visual cortical neurons following BF stimulation have already suggested a prominent role for the GABAergic corticopetal system based on the observation that the effect of BF stimulation on VC cannot be accounted for by cholinergic mechanisms alone (Bhattacharyya et al, 2012(Bhattacharyya et al, , 2013.…”

Basal forebrain contributes to default mode network regulation

“…Another possibility for mediating BF effects on DMN regulation are the GABAergic BF projections, a scenario that is supported by the fact that both parvalbumin and somatostatin GABAergic cells project strongly only to two cortical regions, namely, the ACC and retrosplenial cortex (59), both of which are major DMN nodes. Furthermore, rhythmic activation of BF parvalbumin GABAergic cells has been shown to produce gamma oscillations in the frontal cortex (35). Thus both anatomical and functional substrates by which BF gamma oscillations could influence DMN cortical areas have been documented.…”

“…Anatomical studies have shown that medial frontal cortical structures, including the cingulate cortex, are major targets of both cholinergic and noncholinergic BF neurons (32)(33)(34), such that in anatomical terms the BF possesses considerable connections to DMN frontal cortical structures. It has been shown that the GABAergic corticopetal BF projection, in particular, can produce robust gamma oscillations in cortical targets (35), providing a potential functional pathway by which the BF could influence DMN activation (36).…”

In Memoriam: Robert W. McCarley (1937–2017)

“…Dr. McCarley exhibited constant enthusiasm for cuttingedge research to explore and investigate new ideas. For example, he led a recent optogenetic study demonstrating the role of basal forebrain parvalbumin-expressing GABAergic neurons as the generators of cortical gamma band oscillations, which are important for sensory binding and attention [6]. On the clinical side, his team identified structural abnormalities in the brains of schizophrenic patients, as well as described deficits in cortical gamma band oscillatory activity involved in sensory binding and attention.…”