Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.
Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. In contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioral roles for different dopamine neuron projections in fear extinction learning.
The ability to recognize information incongruous with previous experience is critical for survival, thus novelty signals in the mammalian brain have evolved to enhance attention, perception and memory 1-3 . Although the importance of regions such as the ventral tegmental area 4-6 and locus coeruleus 6,7 in broadly signaling novelty has been well established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information regarding the type of stimuli that drive them 6 . Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain remain unclear. Here we identify a novelty hub in the hypothalamus -the supramammillary nucleus (SuM) 8 . Unique about this region is that it not only responds broadly to novel stimuli, but segregates and selectively routes different types of information to discrete cortical targets, the dentate gyrus (DG) and CA2 fields of the hippocampus, for the modulation of mnemonic processing. Taking advantage of a novel SuM-Cre transgenic mouse, we found that DG-projecting SuM neurons are activated by contextual novelty while the SuM-CA2 circuit is preferentially activated by novel social encounters. Circuitbased manipulation demonstrated that divergent novelty channeling in these projections significantly modifies hippocampal-based contextual or social memory. This content-
Identifying and characterizing brain regions regulating alcohol consumption is beneficial for understanding the mechanisms of alcoholism. To this aim, we first identified brain regions changing in expression of the inducible transcription factor c-Fos in the alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) mice after ethanol consumption. Drinking a 5% ethanol/10% sucrose solution in a 30 min limited access procedure led to induction of c-Fos immunoreactivity in urocortin (Ucn)-positive cells of the Edinger-Westphal nucleus (EW), suppression of c-Fos immunoreactivity in the dorsal portion of the lateral septum (LS) of both strains of mice, and strain-specific suppression in the intermediate portion of the LS and the CA3 hippocampal region. Because the EW sends Ucn projections to the LS, and B6 and D2 mice differ dramatically in EW Ucn expression, we further analyzed the Ucn EW-LS pathway using several genetic approaches. We find that D2 mice have higher numbers of Ucn-immunoreactive processes than B6 mice in the LS and that consumption of ethanol/sucrose in the F2 offspring of a B6D2 intercross positively correlates with Ucn immunoreactivity in the EW and negatively correlates with Ucn immunoreactivity in the LS. In agreement with these findings, we find that alcohol-avoiding male B6.D2 Alcp1 line 2.2 congenic mice have lower Ucn immunoreactivity in the EW than male B6.B6 mice. Finally, we also find that HAP mice, selectively bred for high alcohol preference, have higher Ucn immunoreactivity in EW, than LAP mice, selectively bred for low alcohol preference. Taken together, these studies provide substantial evidence for involvement of the EW-LS Ucn pathway in alcohol consumption.
The Edinger-Westphal nucleus (EW) is a brain region that has recently been implicated as an important novel neural target for ethanol. Thus, the EW is the only brain region consistently showing elevated c-Fos expression following both voluntary and involuntary ethanol administration. Ethanol-induced c-Fos expression in the EW has been shown to occur in urocortin I-positive neurons. Moreover, previous reports using several genetic models have demonstrated that differences in the EW urocortin I system are correlated with ethanol-mediated behaviours such as ethanol-induced hypothermia and ethanol consumption. The aim of this study was to confirm these relationships using a more direct strategy. Thus, ethanol responses were measured following electrolytic lesions of the EW in male C57BL/6J mice. Both EW-lesioned and sham-operated animals were tested for several ethanol sensitivity measures and ethanol consumption in a two-bottle choice test. The results show that lesions of the EW significantly disrupted ethanol-induced hypothermia, while having no effect on pupillary dilation, locomotor activity or ethanol-induced sedation. In addition, EW-lesioned animals showed significantly lower ethanol preference and total ethanol dose consumed in the two-bottle choice test. EW-lesioned animals also consumed less sucrose than sham-operated animals, but did not have altered preferences for sucrose or quinine in a two-bottle choice test. These data support previously observed genetic correlations between EW urocortin I expression and both ethanol-induced hypothermia and ethanol consumption. Taken together, the findings suggest that the EW may function as a sensor for ethanol, which can influence ethanol consumption and preference.
It has been hypothesized that the amnesic effects of alcohol are through selective disruption of hippocampal function. Delay and trace fear conditioning are useful paradigms to investigate hippocampal-dependent and independent forms of memory. With delay fear conditioning, learning of explicit cues does not depend on normal hippocampal function, whereas learning explicit cues in trace fear conditioning does. In both delay and trace fear conditioning, the hippocampus is involved in learning to contextual cues, but it may not be entirely necessary. The present study investigates the effects of alcohol on the acquisition of delay and trace fear conditioning in mice, using freezing as a measure of learning. Male C57BL/6J mice were injected with 0.8 or 1.6 g/kg of 20% v/v alcohol and were immediately exposed to eight tone-footshock pairings in which the conditional stimulus (CS) either coterminated with a footshock unconditional stimulus (US) (delay conditioning) or was separated from the footshock by a 30-s trace interval (trace conditioning). During trace, but not delay fear conditioning, 0.8 g/kg alcohol impaired learning to a tone CS. This dose also impaired context-dependent learning in both procedures (although only slightly for trace fear conditioning). The 1.6 g/kg alcohol exerted a nonselective impairment on learning. The impairment by alcohol of learning to a tone CS when it is hippocampus-dependent, but not when it is hippocampus-independent provides further support for the hypothesis that alcohol exerts a selective effect on hippocampus-dependent learning.
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