Genetic dissection of medial habenula–interpeduncular nucleus pathway function in mice
Open Access
- 1 January 2013
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Behavioral Neuroscience
- Vol. 7, 17
- https://doi.org/10.3389/fnbeh.2013.00017
Abstract
The habenular complex linking forebrain and midbrain structures is subdivided into the medial (mHb) and the lateral nuclei (lHb). The mHb is characterized by the expression of specific nicotinic acetylcholine receptor isoforms and the release of acetylcholine to the interpeduncular nucleus (IPN), the sole output region of the mHb. The specific function of this circuit, however, is poorly understood. Here we generated transgenic mice in which mHb cells were selectively ablated postnatally. These lesions led to large reductions in acetylcholine levels within the IPN. The mutant mice exhibited abnormalities in a wide range of behavioral domains. They tended to be hyperactive during the early night period and were maladapted when repeatedly exposed to new environments. Mutant mice also showed a high rate of premature responses in the 5-choice serial reaction time task (5CSRTT), indicating impulsive and compulsive behavior. Additionally, mice also exhibited delay and effort aversion in a decision-making test, deficits in spatial memory, a subtle increase in anxiety levels, and attenuated sensorimotor gating. IntelliCage studies under social housing conditions confirmed hyperactivity, environmental maladaptation, and impulsive/compulsive behavior, delay discounting, deficits in long-term spatial memory, and reduced flexibility in complex learning paradigms. In 5CSRTT and adaptation tasks, systemic administration of nicotine slowed down a nose-poke reaction and enhanced adaptation in control but not mutant mice. These findings demonstrate that the mHb–IPN pathway plays a crucial role in inhibitory control and cognition-dependent executive functions.Keywords
This publication has 52 references indexed in Scilit:
- Habenular α5 nicotinic receptor subunit signalling controls nicotine intakeNature, 2011
- Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative ReviewNeuropsychopharmacology, 2009
- Smoking and mental illness: results from population surveys in Australia and the United StatesBMC Public Health, 2009
- Two types of dopamine neuron distinctly convey positive and negative motivational signalsNature, 2009
- The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compactaJournal of Comparative Neurology, 2009
- Rodent Habenulo–Interpeduncular Pathway Expresses a Large Variety of Uncommon nAChR Subtypes, But Only the α3β4 and α3β3β4 Subtypes Mediate Acetylcholine ReleaseJournal of Neuroscience, 2009
- Habenula: Crossroad between the Basal Ganglia and the Limbic SystemJournal of Neuroscience, 2008
- High Impulsivity Predicts the Switch to Compulsive Cocaine-TakingScience, 2008
- Impulsivity, Compulsivity, and Habit: The Role of Orbitofrontal Cortex RevisitedBiological Psychiatry, 2008
- Shared Long-Range Regulatory Elements Coordinate Expression of a Gene Cluster Encoding Nicotinic Receptor Heteromeric SubtypesMolecular and Cellular Biology, 2006