Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence

Abstract

As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.

Doxorubicin impairs cognitive function by upregulating AMPAR and NMDAR subunit expression and increasing neuroinflammation, oxidative stress, and apoptosis in the brain

“…In addition, NMDARs play a vital role to synaptic plasticity and cognitive function ( Brothwell et al, 2008 ; Suzuki et al, 2023 ). In cases of prenatal nicotine or alcohol exposure, NMDAR expression is reduced, resulting in memory deficits and impaired LTP ( Alhowail et al, 2021 ; Alhowail, 2022 ; Polli and Kohlmeier, 2022 ). Similarly, blocking NMDAR expression reduces LTP induction and results in memory impairment ( Yang et al, 2018 ).…”

“…Postsynaptic membrane depolarization by AMPARs removes this blockade, permitting Ca 2+ influx, which is essential for downstream memory formation ( Luscher and Malenka, 2012 ). AMPARs comprise four subunits (GluA1–4), which are differentially expressed ( Bhattacharya et al, 2017 ; Polli and Kohlmeier, 2022 ). In the adult brain, GluA1 is permeable to Ca 2+ ; however, GluA2 is not permeable to Ca 2+ because of the presence of arginine in its receptor, which blocks Ca 2+ permeability through AMPARs ( Wright and Vissel, 2012 ; Livingstone et al, 2021 ).…”

Axonal α7* nicotinic acetylcholine receptors modulate glutamatergic signaling and synaptic vesicle organization in ventral hippocampal projections

“…The importance of these functions is underscored by the connections between disruption in the cholinergic system and conditions ranging from thought disorders to cognitive impairment and dementia. Understanding how cholinergic inputs influence various forebrain circuits is essential to defining the role of acetylcholine in these conditions (Freedman et al, 2001;Mathew et al, 2007;Barreto et al, 2015;Lim et al, 2015;Alber et al, 2020;Bohnen et al, 2022;Polli and Kohlmeier, 2022).…”