Diabetes is far more prevalent in smokers than non-smokers, but little is known about underlying mechanisms of vulnerability. Here, we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb), where it regulates the function of nicotinic acetylcholine receptors. Inhibition of Tcf7l2 signaling in the mHb increases nicotine intake in mice and rats. Nicotine elevates blood glucose levels through a Tcf7l2-dependent stimulatory action on the mHb. Virus tracing identifies a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show elevated circulating levels of glucagon and insulin and diabetes-like dysregulation of blood glucose homeostasis. In contrast, Tcf7l2 mut rats are resistant to these actions of nicotine. Our findings suggest that Tcf7l2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

B. b2* nAChRs Regulate Affective but Not Physical Components of Nicotine Withdrawal . . . C. Other nAChR Subtypes Contribute to Affective Components of Nicotine Withdrawal . . . . D. Dopamine Transmission Contributes to Affective Components of Nicotine Withdrawal . . . E. b4* nAChRs Regulate Physical but Not Affective Components of Nicotine Withdrawal . . .

Allelic variation in CHRNA3, the gene encoding the a3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for a3-containing (a3p) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. a3p nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3 tm1.1Hwrt hypomorphic mice, which express constitutively low levels of a3p nAChRs, self-administer greater quantities of nicotine (0.4 mg kg 21 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg 21 per infusion). Using whole-cell recordings, we found that the a3b4p nAChR-selective antagonist a-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the a3b2p nAChR-selective antagonist a-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of a-conotoxin AuIB (10 lM) but not a-conotoxin MII (10 lM) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that a3b4p nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.

Maternal choline supplementation (MCS) improves cognition in Alzheimer's disease (AD). However, the effects of MCS on neuronal hyperexcitability in AD are unknown. Therefore, we investigated the effects of MCS in a well-established mouse model of AD, the Tg2576 mouse. Like many AD mouse models and patients, Tg2576 mice exhibit hyperexcitability, typically generalized EEG spikes (interictal spikes; IIS). Hyperexcitability is also reflected by elevated expression of the transcription factor deltaFosB in the principal cells of the dentate gyrus (DG), granule cells (GCs). We also studied the hilus of the DG because hilar neurons regulate GC excitability. We found that hilar neurons reduce expression of the neuronal marker NeuN in Tg2576 mice, which other studies have shown is a sign of oxidative stress or pathology. Tg2576 breeding pairs received a diet with a relatively low, intermediate or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC deltaFosB expression was reduced, and NeuN expression restored. Spatial memory improved. In contrast, offspring of mice fed the relatively low choline diet had several adverse effects, such as increased mortality, suggesting poor health. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have negative consequences. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, and spatial memory in an animal model of AD.

Two experiments with Long-Evans rats examined the potential independence of learning about different features of food reward, namely, "what" reward is to be expected and "when" it will occur. This was examined by investigating the effects of selective reward devaluation upon responding in an instrumental peak timing task in Experiment 1 and by exploring the effects of pre-training lesions targeting the basolateral amygdala (BLA) upon the selective reward devaluation effect and interval timing in a Pavlovian peak timing task in Experiment 2. In both tasks, two stimuli, each 60 s long, signaled that qualitatively distinct rewards (different flavored food pellets) could occur after 20 s. Responding on non-rewarded probe trials displayed the characteristic peak timing function with mean responding gradually increasing and peaking at approximately 20 s before more gradually declining thereafter. One of the rewards was then independently paired repeatedly with LiCl injections in order to devalue it whereas the other reward was unpaired with these injections. In a final set of test sessions in which both stimuli were presented without rewards, it was observed that responding was selectively reduced in the presence of the stimulus signaling the devalued reward compared to the stimulus signaling the still valued reward. Moreover, the timing function was mostly unaltered by this devaluation manipulation. Experiment 2 showed that pre-training BLA lesions abolished this selective reward devaluation effect, but it had no impact on peak timing functions shown by the two stimuli. It appears from these data that learning about "what" and "when" features of reward may entail separate underlying neural systems.