Role of the locus coeruleus and basal forebrain in arousal and attention

Dual orexin/hypocretin receptor antagonism attenuates attentional impairments in an NMDA receptor hypofunction model of schizophrenia

“…In addition to putatively anticholinergic effects in the BF, dual orexin receptor antagonism may have indirectly addressed dizocilpine-induced dysfunctions of signal-driven input selection and cortical vigilance networks stemming via various non-cholinergic loci in the mesocorticolimbic system, including PV+ GABAergic neurons of the BF. These fast-spiking neurons - which have recently been shown to quicken reaction times in a rodent psychomotor vigilance task when optogenetically stimulated [75, 76] - are depolarized by orexins and are themselves sufficient to stimulate cortical arousal when exposed to OxA in animals with lesions to corticopetal cholinergic projections [43, 77]. Thus, frontocortical activation may be suppressed when blocking orexin receptors expressed on these neurons as well as orexin receptors located on cortical glutamatergic outputs to the BF, which synapse exclusively with these PV+ GABAergic neurons [78, 79].…”

Adaptive mechanisms facilitate robust performance in noise and in reverberation in an auditory categorization model

“…For example, vasoactive-intestinal-peptide-expressing neurons, which are recruited by reinforcement signals (e.g., reward and punishment during learning), suppress subtypes of inhibitory interneurons, thus, in turn, disinhibiting principal neurons in the cortex during task engagement (Pi et al, 2013). Two other relevant pathways that also modulate cortical excitability involve the noradrenergic locus coeruleus (Maness et al, 2022; Martins and Froemke, 2015) and the cholinergic basal forebrain (Froemke et al, 2007; Kuchibhotla et al, 2017; Letzkus et al, 2011; Pi et al, 2013). While both these pathways generally modulate auditory cortical activity globally (i.e., in a frequency-independent manner), which is similar to our implementation of top-down modulation (e.g., FDs for all calls were similarly modulated at the same noise level or reverberation condition), it remains to be seen whether other top-down mechanisms exist that are optimized to the spectrotemporal properties of the incoming sound.…”

“…Biologically, the reduction in threshold with noise level could be accomplished by increasing the excitability of FD neurons, i.e., by reducing the distance between each neuron's resting membrane potential and spike threshold. In a neural circuit, this could be accomplished by disinhibiting these neurons, perhaps through the activation of specific cortical cell types by cholinergic or noradrenergic inputs (Froemke et al, 2007;Kuchibhotla et al, 2017;Letzkus et al, 2011;Maness et al, 2022;Martins and Froemke, 2015;Pi et al, 2013). Next, we quantified model performance as a result of top-down modulation of FDs.…”

“…Finally, recent studies have shown that attention-mediated feedback can control the excitability of cortical neurons to aid performance in challenging listening environments (Fu et al, 2014; Kerlin et al, 2010). Specifically, arousal-related noradrenergic input from locus coeruleus (Maness et al, 2022; Martins and Froemke, 2015) as well as cholinergic inputs from the basal forebrain (Froemke et al, 2007; Kuchibhotla et al, 2017; Letzkus et al, 2011) can increase the excitability of cortical principal neurons, often by providing disinhibition by suppressing the activity of inhibitory interneuron subtypes (Pi et al, 2013). We implemented this top-down pathway as a modulation of the threshold of FDs.…”

Effect of cognitive reserve on physiological measures of cognitive workload in older adults with cognitive impairments

“…Pupillary dilation in response to cognitive workload is mainly mediated through the locus coeruleus [45]. The locus coeruleus is the main supplier of noradrenaline in the brain and critical in the regulation of physiological arousal and cognition [46]. In vivo and post-mortem imaging studies demonstrate that older adults with cognitive impairments exhibit decreased neuronal density and early tau accumulation in the locus coeruleus [47].…”