The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Abstract

The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA A receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.basic helix-loop-helix ͉ haploinsufficiency T he amygdala is an almond-shaped brain structure that integrates emotional learning and other emotional responses such as fear perception. The role of the amygdala in fear perception and response was established through lesioning studies in animals and confirmed through positron emission tomography and functional magnetic resonance imaging in normal human subjects and in schizophrenic patients with deficits in fear processing (1-9).We previously reported that neuroD2-null mice on a mixed genetic background are indistinguishable from littermates at birth, but fail to thrive and die within weeks of birth. Before death, nullizygous mice develop ataxia, seizures, cerebellar degeneration, and growth retardation. NeuroD2 heterozygotes appear normal as adults, but have reduced seizure threshold and mild ataxia. We observed aggressive behavior between neuroD2 heterozygotes, which prompted us to evaluate the function and structure of the amygdala and related limbic system brain regions that control aggression, fear, and other emotions. Unconditioned fear (also referred to as anxiety or risk perception) is the response to environmental cues that signal danger. The basolateral amygdala and ventral subiculum of hippocampus are involved in unconditioned fear responses; however, the neuronal circuitry and molecular mechanisms are poorly understood (10).In contrast to unconditioned fear, the neurochemical and molecular basis of emotional learning related to conditioned fear are being elucidated through studies that evaluate fear conditioning in the context of pharmacologic or genetic manipulation of neurotransmitter receptors and second messengers. Fear conditioning involves coupling a neutral conditioned stimulus (CS) such as an audible tone with a noxious unconditioned stimulus (US) such as foot shock and observing that after training and rest periods, that the CS alone is sufficient to elicit behavioral (e.g., freezing) and autonomic responses (11,12). During the training and rest period, the lateral amygdala acquires and consolidates short-and long-term memory that associates the conditioned and unconditioned stimuli through a process known as emotional learning.The acquisition phas...

Variation in Mouse Basolateral Amygdala Volume is Associated With Differences in Stress Reactivity and Fear Learning

“…Differences in fear expression between volume BLA groups were found both for conditioned fear to discrete (auditory cue) and compound (context) stimuli, which is consistent with the ability of BLA lesions (Goosens and Maren, 2001) and gene knockout-induced gross disruption of BLA (Lin et al, 2005) to impair both forms of associative fear memory. Interestingly however, there was a significant genetic correlation between BLA volume-varying BXD lines and cued, but not contextual, conditioned fear.…”

A possible impact of the neuroD2 transcription factor on the development of drug abusing behavior

“…Although the major part of the reward system in addiction is the dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAS), also dopaminergic projections from the VTA to the cortex, as well as massive glutamatergic inputs to the VTA from the cortex, hippocampus and amygdala are involved in the mediation of reward. 5 Interestingly, these structures and neurotransmitter systems have been implicated in aspects of reward evaluation, learning and memory 8 characteristics that have been reported by Lin et al 1 as being associated with the neuroD2 gene. Diminished neuroD2 levels are related not only to decreased amounts of the AMPA and GABA-A receptors in mice but also to an increased risk behavior.…”

“…3 Lin et al could demonstrate that neuroD2 is necessary not only for the amygdala development in mice but also that the dose of the neuroD2 gene is critical for the regulation of molecules that underlie emotional learning, as the AMPA receptor, the gamma aminobutyric acid (GABA)-A receptor and Ulip, a protein that is involved in neuronal plasticity. 1 Furthermore, neuroD2 heterozygous mice showed a decreased response to fear conditioning and unconditioned fear analysis. 1 There is increasing evidence that addiction not only emerges from neuronal mechanisms of learning and memory, with involvement of the GABAergic and glutamatergic systems, but also represents a risktaking behavior itself.…”

“…1 Furthermore, neuroD2 heterozygous mice showed a decreased response to fear conditioning and unconditioned fear analysis. 1 There is increasing evidence that addiction not only emerges from neuronal mechanisms of learning and memory, with involvement of the GABAergic and glutamatergic systems, but also represents a risktaking behavior itself. [4][5][6] Additionally, suicidal behavior has a high comorbidity with risk-related personality traits, with the highest risk-taking behavior in completed suicide by violent means.…”

“…A possible impact of the neuroD2 transcription factor on the development of drug abusing behavior A recent study by Lin et al 1 has shown that the transcription factor neuroD2 regulates amygdala development and emotional learning in mice. In neuroD2-null mice, the lateral and basolateral amygdala was undeveloped and neuroD2 heterozygous mice had fewer neurons in this region.…”