Abstract
The subthalamic nucleus (STN), a key component of the basal ganglia circuitry, receives inputs from broad cerebral cortical areas and relays cortical activity to subcortical structures. Recent human and animal studies have suggested that executive function, which is assumed to consist of a set of different cognitive processes for controlling behavior, depends on precise information processing between the cerebral cortex and subcortical structures, leading to the idea that the STN contains neurons that transmit the information required for cognitive processing through their activity, and is involved in such cognitive control directly and dynamically. On the other hand, the STN activity also affects intracellular signal transduction and gene expression profiles influencing plasticity in other basal ganglia components. The STN may also indirectly contribute to information processing for cognitive control in other brain areas by regulating slower signaling mechanisms. However, the precise correspondence and causal relationship between the STN activity and cognitive processes are not fully understood. To address how the STN activity is involved in cognitive processes for controlling behavior, we applied Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic manipulation of neural activity to behavioral analysis using a touchscreen operant platform. We subjected mice selectively expressing DREADD receptors in the STN neurons to a five-choice serial reaction time task, which has been developed to quantitatively measure executive function. Chemogenetic suppression of the STN activity reversibly impaired attention, especially required under highly demanding conditions, and increased impulsivity but not compulsivity. These findings, taken together with the results of previous lesion studies, suggest that the STN activity, directly and indirectly, participates in cognitive processing for controlling behavior, and dynamically regulates specific types of subprocesses in cognitive control probably through fast synaptic transmission.
Highlights
Executive function—cognitive control of behavior—depends on the integrative properties of interconnected circuits consisting of the cerebral cortex and subcortical structures
We selectively introduced hM4Di-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) in subthalamic nucleus (STN) neurons by a combinatorial gene expression system utilizing an adeno-associated virus (AAV) vector with double-floxed inverted open reading frames (DIO), which is transcriptionally activated by Cre-mediated recombination (Schnütgen et al, 2003), and a paired-like homeodomain transcription factor 2-Cre (Pitx2-Cre) mouse line as a Cre-driver (Liu et al, 2003; Martin et al, 2004; Skidmore et al, 2008; Schweizer et al, 2014, 2016)
To genetically manipulate the STN neurons without affecting neighboring brain areas, we applied a combinatorial gene expression system utilizing an AAV-DIO vector, which is transcriptionally activated by Cre-mediated recombination (Figure 1A), and the Pitx2-Cre mouse line as a Cre-driver (Liu et al, 2003; Martin et al, 2004; Skidmore et al, 2008; Schweizer et al, 2014, 2016)
Summary
Executive function—cognitive control of behavior—depends on the integrative properties of interconnected circuits consisting of the cerebral cortex and subcortical structures. Among the cortico-subcortical circuitry, the subthalamic nucleus (STN), which is mainly composed of glutamatergic neurons (BarrosoChinea et al, 2007; Koshimizu et al, 2013) and relays cortical activity to subcortical structures as a component of the basal ganglia (Parent and Hazrati, 1995; Nambu et al, 2002), is postulated to play a pivotal role in cognitive processes for controlling behavior (Baunez and Robbins, 1997; Baunez et al, 2001; Aron and Poldrack, 2006; Zaghloul et al, 2012; Weintraub and Zaghloul, 2013). Anatomical connectivity of the STN and functional manipulation of its activity support the idea that the STN functions as an integrative node that links cognitive processing with motor and other functions, and the activity state of the STN neurons is critical for cognitive control (Aron and Poldrack, 2006; Zaghloul et al, 2012; Weintraub and Zaghloul, 2013)
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