Subcortical control of the default mode network: Role of the basal forebrain and implications for neuropsychiatric disorders

Abstract

The precise interplay between large-scale functional neural systems throughout the brain is essential for performance of cognitive processes. In this review we focus on the default mode network (DMN), one such functional network that is active during periods of quiet wakefulness and believed to be involved in introspection and planning. Abnormalities in DMN functional connectivity and activation appear across many neuropsychiatric disorders, including schizophrenia. Recent evidence suggests subcortical regions including the basal forebrain are functionally and structurally important for regulation of DMN activity. Within the basal forebrain, subregions like the ventral pallidum may influence DMN activity and the nucleus basalis of Meynert can inhibit switching between brain networks. Interactions between DMN and other functional networks including the medial frontoparietal network (default), lateral frontoparietal network (control), midcingulo-insular network (salience), and dorsal frontoparietal network (attention) are also discussed in the context of neuropsychiatric disorders. Several subtypes of basal forebrain neurons have been identified including basal forebrain parvalbumin-containing or somatostatin-containing neurons which can regulate cortical gamma band oscillations and DMN-like behaviors, and basal forebrain cholinergic neurons which might gate access to sensory information during reinforcement learning. In this review, we explore this evidence, discuss the clinical implications on neuropsychiatric disorders, and compare neuroanatomy in the human vs rodent DMN. Finally, we address technological advancements which could help provide a more complete understanding of modulation of DMN function and describe newly identified BF therapeutic targets that could potentially help restore DMN-associated functional deficits in patients with a variety of neuropsychiatric disorders.

Keywords: Brain networks; Cholinergic neurons; Functional magnetic resonance imaging; Medial frontoparietal network; Parvalbumin; Schizophrenia.

Fig. 1.. Diagram of DMN-relevant regions in human and mouse brain.

Human (A) and mouse (B) brain represented as midline sagittal slice (left) and lateral view (right). Homologous areas associated with the DMN that are visible in the sagittal view (left) include: 1) the human prefrontal cortex consisting of medial prefrontal cortex (mPFC) and dorsal prefrontal cortex (dPFC) and mouse medial orbital cortex (MO), prelimbic cortex (PrL), and anterior cingulate cortex (ACC), 2) human posterior cingulate (PCC) including precuneus (PCu) and retrosplenial cortex (RSP) and mouse medial cingulate cortex (MCC) and granular/dysgranular retrosplenial cortex (RSP), 3) thalamus (T), and 4) basal forebrain (BF). Lateral view: 5) human ventrolateral prefrontal cortex (VLPFC) within the inferior frontal gyrus, 6) human lateral temporal cortex (LTC) and mouse auditory/temporal association cortex (TeA), 7) human inferior parietal lobe (IPL) which includes the angular gyms (AG) and mouse posterior parietal cortex (PPC) with secondary visual cortex. Figure created in BioRender.com.

Fig. 2.. Stimulation or Inhibition of BF Cell types: Impact on DMN-like Activity and Behaviors.

A) Stimulation of BF PV Neurons at gamma frequencies entrains GBO’s in the ACC and induces and maintains DMN-like behaviors including self-directed grooming, enhanced internal focus, and reduced attention to external stimuli (Lozano-Montes et al., 2020; Klaassen et al., 2021). In the absence of stimulation, DMN-like behavioral contexts induce coordinated GBO’s in the BF and ACC (Nair et al., 2018). B) Simultaneous tonic inhibition of BF cholinergic and GABAergic neurons suppresses DMN-like behaviors and reduces spontaneous GBO power in both the BF and ACC (Klaassen et al., 2021). C) Tonic stimulation of BF PV neurons (McNally et al., 2021) or disinhibition of BF neurons (unspecified cell type) through BF SST inhibition (Espinosa et al., 2019a, 2019b) has consequences that may be attributable to DMN activity. Either treatment likely results in enhanced BF PV activity due to local circuit interactions between BF cell types (Yang et al., 2017). Pro-DMN-like phenotypes include enhanced spontaneous GBO power in the ACC, reduced external task-elicited GBO’s in the ACC, and reduced novel object recognition performance suggesting impaired external attention (Espinosa et al., 2019a, 2019b; McNally et al., 2021). Anti-DMN-like phenotypes include enhanced locomotion and reduced GBO coherence between the BF and ACC. In summary, the BF appears critical for induction, maintenance, and/or suppression of DMN activity likely through specific circuitry where cortically projecting PV containing neurons play a privileged role. Figure created in BioRender.com. Abbreviations: anterior cingulate cortex (ACC), auditory steady state response (ASSR), basal forebrain (BF), cholinergic (ChAT), diagonal band (DB), default mode network (DMN), gamma-aminobutyric acid (GABA), gamma band oscillations (GBO), magnocellular preoptic area (MCPO), parvalbumin (PV), prelimbic (PrL), somatostatin (SST), ventral pallidum (VP).