Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.

The current longitudinal study examined factors (sex, physical function, response to novelty, ability to adapt to a shift in light/dark cycle, brain connectivity), which might predict the emergence of impaired memory during aging. Male and female Fisher 344 rats were tested at 6, 12, and 18 months of age. Impaired spatial memory developed in middle-age (12 months), particularly in males, and the propensity for impairment increased with advanced age. A reduced response to novelty was observed over the course of aging, which is inconsistent with cross-sectional studies. This divergence likely resulted from differences in the history of environmental enrichment/impoverishment for cross-sectional and longitudinal studies. Animals that exhibited lower level exploration of the inner region on the open field test exhibited better memory at 12 months. Furthermore, males that exhibited a longer latency to enter a novel environment at 6 months, exhibited better memory at 12 months. For females, memory at 12 months was correlated with the ability to behaviorally adapt to a shift in light/dark cycle. Functional magnetic resonance imaging of the brain, conducted at 12 months, indicated that the decline in memory was associated with altered functional connectivity within different memory systems, most notably between the hippocampus and multiple regions such as the retrosplenial cortex, thalamus, striatum, and amygdala. Overall, some factors, specifically response to novelty at an early age and the capacity to adapt to shifts in light cycle, predicted spatial memory in middle-age, and spatial memory is associated with corresponding changes in brain connectivity. We discuss similarities and differences related to previous longitudinal and cross-sectional studies, as well as the role of sex differences in providing a theoretical framework to guide future longitudinal research on the trajectory of cognitive decline. In addition to demonstrating the power of longitudinal studies, these data highlight the importance of middle-age for identifying potential predictive indicators of sexual dimorphism in the trajectory in brain and cognitive aging.

Significance: Oxidative stress increases in the brain with aging and neurodegenerative diseases. Previous work emphasized irreversible oxidative damage in relation to cognitive impairment. This research has evolved to consider a continuum of alterations, from redox signaling to oxidative damage, which provides a basis for understanding the onset and progression of cognitive impairment. This review provides an update on research linking redox signaling to altered function of neural circuits involved in information processing and memory.Recent Advances: Starting in middle age, redox signaling triggers changes in nervous system physiology described as senescent physiology. Hippocampal senescent physiology involves decreased cell excitability, altered synaptic plasticity, and decreased synaptic transmission. Recent studies indicate N-methyl-d-aspartate and ryanodine receptors and Ca2+ signaling molecules as molecular substrates of redox-mediated senescent physiology.Critical Issues: We review redox homeostasis mechanisms and consider the chemical character of reactive oxygen and nitrogen species and their role in regulating different transmitter systems. In this regard, senescent physiology may represent the co-opting of pathways normally responsible for feedback regulation of synaptic transmission. Furthermore, differences across transmitter systems may underlie differential vulnerability of brain regions and neuronal circuits to aging and disease.Future Directions: It will be important to identify the intrinsic mechanisms for the shift in oxidative/reductive processes. Intrinsic mechanism will depend on the transmitter system, oxidative stressors, and expression/activity of antioxidant enzymes. In addition, it will be important to identify how intrinsic processes interact with other aging factors, including changes in inflammatory or hormonal signals. Antioxid. Redox Signal. 28, 1724–1745.

The role of microglia in mediating age‐related changes in cognition and hippocampal synaptic function was examined by microglial depletion and replenishment using PLX3397. We observed age‐related differences in microglial number and morphology, as well as increased Iba‐1 expression, indicating microglial activation. PLX3397 treatment decreased microglial number, with aged rats exhibiting the lowest density. Young rats exhibited increased expression of pro‐inflammatory cytokines during depletion and repopulation and maintenance of Iba‐1 levels despite reduced microglial number. For aged rats, several cytokines increased with depletion and recovered during repopulation; however, aged rats did not fully recover microglial cell number or Iba‐1 expression during repopulation, with a recovery comparable to young control levels rather than aged controls. Hippocampal CA3–CA1 synaptic transmission was impaired with age, and microglial depletion was associated with decreased total synaptic transmission in young and aged rats. A robust decline in N‐methyl‐d‐aspartate‐receptor‐mediated synaptic transmission arose in young depleted rats specifically. Microglial replenishment normalized depletion‐induced synaptic function to control levels; however, recovery of aged animals did not mirror young. Microglial depletion was associated with decreased context‐object discrimination memory in both age groups, which recovered with microglial repopulation. Aged rats displayed impaired contextual and cued fear memory, and microglial replenishment did not recover their memory to the level of young. The current study indicates that cognitive function and synaptic transmission benefit from the support of aged microglia and are hindered by removal of these cells. Replenishment of microglia in aging did not ameliorate age‐related cognitive impairments or senescent synaptic function.

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