Nicotine on the developing brain.

Developmental periods such as gestation and adolescence have enhanced plasticity leaving the brain vulnerable to harmful effects from nicotine use. Proper brain maturation and circuit organization is critical for normal physiological and behavioral outcomes. Although cigarette smoking has declined in popularity, noncombustible nicotine products are readily used. The misperceived safety of these alternatives lead to widespread use among vulnerable populations such as pregnant women and adolescents. Nicotine exposure during these sensitive developmental windows is detrimental to cardiorespiratory function, learning and memory, executive function, and reward related circuitry. In this review, we will discuss clinical and preclinical evidence of the adverse alterations in the brain and behavior following nicotine exposure. Time-dependent nicotine-induced changes in reward related brain regions and drug reward behaviors will be discussed and highlight unique sensitivities within a developmental period. We will also review long lasting effects of developmental exposure persisting into adulthood, along with permanent epigenetic changes in the genome which can be passed to future generations. Taken together, it is critical to evaluate the consequences of nicotine exposure during these vulnerable developmental windows due to its direct impact on cognition, potential trajectories for other substance use, and implicated mechanisms for the neurobiology of substance use disorders.

CX3CR1 mutation alters synaptic and astrocytic protein expression, topographic gradients, and response latencies in the auditory brainstem.

The precise and specialized circuitry in the auditory brainstem develops through adaptations of cellular and molecular signaling. We previously showed that elimination of microglia during development impairs synaptic pruning that leads to maturation of the calyx of Held, a large encapsulating synapse that terminates on neurons of the medial nucleus of the trapezoid body (MNTB). Microglia depletion also led to a decrease in glial fibrillary acidic protein (GFAP), a marker for mature astrocytes. Here, we investigated the role of signaling through the fractalkine receptor (CX3CR1), which is expressed by microglia and mediates communication with neurons. CX3CR1-/- and wild-type mice were studied before and after hearing onset and at 9 weeks of age. Levels of GFAP were significantly increased in the MNTB in mutants at 9 weeks. Pruning was unaffected at the calyx of Held, but we found an increase in expression of glycinergic synaptic marker in mutant mice at P14, suggesting an effect on maturation of inhibitory inputs. We observed disrupted tonotopic gradients of neuron and calyx size in MNTB in mutant mice. Auditory brainstem recording (ABR) revealed that CX3CR1-/- mice had normal thresholds and amplitudes but decreased latencies and interpeak latencies, particularly for the highest frequencies. These results demonstrate that disruption of fractalkine signaling has a significant effect on auditory brainstem development. Our findings highlight the importance of neuron-microglia-astrocyte communication in pruning of inhibitory synapses and establishment of tonotopic gradients early in postnatal development.