Papers by E. Zayra Millan
Frontiers in Neuroscience, 2015
Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive r... more Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two-thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons.
Neuropsychopharmacology, 2015
Neurobiological mechanisms that influence behavior in the presence of alcohol-associated stimuli ... more Neurobiological mechanisms that influence behavior in the presence of alcohol-associated stimuli involve processes that organize behavior during the presence of these cues and separately, regulation of behavior in their absence. However little is known of the anatomical structures that might mediate this regulation. Here we examined nucleus accumbens shell (AcbSh) as a possible neural substrate mediating behavior modulation triggered by the presence and absence of alcohol-associated environmental cues and contexts. We also examined subregions of basal amygdala nuclei - rostral basolateral (BLA) and basal posterior (BAP) - since they provide a major source of glutamatergic input to the AcbSh. Animals were trained to associate an auditory conditioning stimulus with alcohol in a discriminative context and then subsequently tested for conditioned port-entries across contexts either previously associated or not associated with alcohol. We found that on test to the alcohol cue alone, AcbSh inactivation prevented conditioned port-entries in contexts that either were associated with alcohol or were novel, while also increasing unconditioned port-entries during the intertrial intervals. When tested to alcohol-reinforced cues, AcbSh inactivation produced more cue-trial omissions and elevated unconditioned port-entries. Interestingly, BLA and BAP inactivation produced dissociable effects. BAP but not BLA increased unconditioned port-entries, while both manipulations prevented conditioned port-entries during the alcohol-cue. We conclude that AcbSh is necessary for modulating control over behavior otherwise guided by the presence of alcohol-predictive environmental stimuli and contexts. Moreover, this role may involve integration of functionally segregated inputs from rostral and posterior portions of basal amygdala nuclei.Neuropsychopharmacology accepted article preview online, 15 April 2015. doi:10.1038/npp.2015.102.
Neurobiology of Learning and Memory, 2013
In four experiments we studied the impact of retrieval-extinction training on the extinction and ... more In four experiments we studied the impact of retrieval-extinction training on the extinction and reinstatement of alcoholic beer seeking. Experiment 1 showed that preceding daily extinction sessions with a brief (10 min) extinction session (retrieval-extinction) attenuated the context-induced reinstatement of alcoholic beer seeking, thereby replicating and extending the findings of Xue et al. . Experiment 2 then showed that the retrieval-extinction manipulation could attenuate the reinstatement produced by reversible inactivation of the nucleus accumbens shell prior to test. Experiment 3 showed that a modified extinction protocol that involved a reversed retrieval (i.e. extinction then retrieval) was also able to attenuate context-induced reinstatement. Finally, Experiment 4 showed that the extinction-retrieval manipulation facilitated the reacquisition of alcoholic beer seeking as evidenced by increased breakpoints and responses during tests under a progressive ratio schedule. Taken together, these findings show that retrieval-extinction training protocols can alter the propensity to reinstate extinguished drug seeking but that these alterations are not always protective. These findings are inconsistent with accounts of the retrieval-extinction manipulation in terms of memory reconsolidation and deepened extinction. Instead, they are consistent with the notion that this manipulation increases the sensitivity of animals to the contingencies in effect during testing.
Learning & Memory, 2011
Abstract Extinction is the reduction in drug seeking when the contingency between drug seeking be... more Abstract Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4%(v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B). Rats were subsequently tested in the training context, A (ABA), or the extinction context, B (ABB). Pre-test injections of the glutamate AMPA receptor antagonist, NBQX (1 µg) into AcbSh ...
Cellular and Molecular Life Sciences, 2012
The hypothalamus is a neural structure critical for expression of motivated behaviours that ensur... more The hypothalamus is a neural structure critical for expression of motivated behaviours that ensure survival of the individual and the species. It is a heterogeneous structure, generally recognised to have four distinct regions in the rostrocaudal axis (preoptic, supraoptic, tuberal and mammillary). The tuberal hypothalamus in particular has been implicated in the neural control of appetitive motivation, including feeding and drug seeking. Here we review the role of the tuberal hypothalamus in appetitive motivation. First, we review evidence that different regions of the hypothalamus exert opposing control over feeding. We then review evidence that a similar bi-directional regulation characterises hypothalamic contributions to drug seeking and reward seeking. Lateral regions of the dorsal tuberal hypothalamus are important for promoting reinstatement of drug seeking, whereas medial regions of the dorsal tuberal hypothalamus are important for inhibiting this drug seeking after extinction training. Finally, we review evidence that these different roles for medial versus lateral dorsal tuberal hypothalamus in promoting or preventing reinstatement of drug seeking are mediated, at least in part, by different populations of hypothalamic neurons as well as the neural circuits in which they are located.
We investigated the impact of cocaine- and amphetamine-regulated transcript (CART) in the nucleus... more We investigated the impact of cocaine- and amphetamine-regulated transcript (CART) in the nucleus accumbens shell (AcbSh) on context-induced reinstatement of alcoholic beer-seeking. Rats were trained to respond for 4% (vol/vol) alcoholic beer in one context (A) followed by extinction in a second context (B). Rats were subsequently tested for renewal of extinguished responding in the training context (A). Return to the training context elicited responding (reinstatement), whereas intra-AcbSh injections of CART (55-102) attenuated reinstatement without affecting general behavioral activity (Experiment 1). CART (55-102) attenuated reinstatement dose-dependently across the 0.025 - 2.5 μg range (Experiment 2), and no effect was observed with the inactive CART (1-27) fragment (Experiment 3). Together, these findings suggest that intra-AcbSh CART (55-102) modulates the impact of drug-associated environments on reward seeking behavior.
Journal of Neuroscience, 2010
The nucleus accumbens shell (AcbSh) is required to inhibit drug seeking after extinction training... more The nucleus accumbens shell (AcbSh) is required to inhibit drug seeking after extinction training. Conversely, the lateral hypothalamus (LH), which receives projections from AcbSh, mediates reinstatement of previously extinguished drug seeking. We hypothesized that reversible inactivation of AcbSh using GABA agonists (baclofen/muscimol) would reinstate extinguished alcohol seeking and increase neuronal activation in LH. Rats underwent self-administration training for 4% (v/v) alcoholic beer followed by extinction. AcbSh inactivation reinstated extinguished alcohol seeking when infusions were made after, but not before, extinction training. We then used immunohistochemical detection of c-Fos as a marker of neuronal activity, combined with immunohistochemical detection of the orexin and cocaine-and amphetamine-related transcript (CART) peptides, to study the profile and phenotype of neural activation during reinstatement produced by AcbSh inactivation.
Behavioural Brain Research, 2011
Drug seeking behavior can be reduced or inhibited via extinction. The brain mechanisms for extinc... more Drug seeking behavior can be reduced or inhibited via extinction. The brain mechanisms for extinction of drug seeking are poorly understood but are of significant interest because of their potential to identify novel approaches that promote abstinence from drug taking. Here we review recent literature on the neural mechanisms for extinction in drug self-administration paradigms. First, we consider the brain regions important for extinction of drug seeking. Functional inactivation studies have identified infralimbic prefrontal cortex, nucleus accumbens shell, as well as medial dorsal hypothalamus in the expression of extinction of drug seeking. These structures have been implicated in extinction expression across several reinforcers including cocaine, heroin, and alcohol. Second, we consider molecular studies which show that extinction training is associated with plasticity in glutamatergic signaling in both nucleus accumbens shell and core, and that this training may reverse or ameliorate the neuroadaptations produced by chronic drug exposure and spontaneous withdrawal. Finally, we consider the neural circuitry for extinction of drug seeking. Functional disconnection and neuroanatomical tracing studies show that extinction expression depends, at least in part, on cortico-striatal-hypothalamic and cortico-hypothalalmic-thalamic pathways. Moreover, they indicate that the expression of extinction and reinstatement of drug seeking may depend on parallel pathways that converge within lateral hypothalamus and paraventricular thalamus. (G.P. McNally).
Behavioural Brain Research, 2011
On April 24-27, 2010, the Motivational Neuronal Networks meeting took place in Wrightsville Beach... more On April 24-27, 2010, the Motivational Neuronal Networks meeting took place in Wrightsville Beach, North Carolina. The conference was devoted to "Emerging, re-emerging, and forgotten brain areas" of the reward circuit. A central feature of the conference was four scholarly discussions of cutting-edge topics related to the conference's theme. These discussions form the basis of the present review, which summarizes areas of consensus and controversy, and serves as a roadmap for the next several years of research.
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Papers by E. Zayra Millan