Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice

Lee, Sukchan; Ahmed, Touqeer; Lee, Soo-Jung; Kim, Huisu; Choi, Sukwoo; Kim, Duk Soo; Kim, Sang Jeong; Cho, Jeiwon; Shin, Hee Sup

doi:10.1038/nn.2999

Cited by 77 publications

(71 citation statements)

References 45 publications

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“…Recent data, however, suggest that interruption of function may not take place because in the human STN 100-Hz simulation did not silence the activity of STN neurons (30). In our previous study (31), high-frequency stimulation in the thalamus did not cause interruption of the function, further suggesting the validity of this approach. Irrespective of the exact mechanisms the electrical stimulation showed a clear lateralized effect, which was in the opposite direction than the inactivation.…”

Section: Discussionmentioning

confidence: 66%

Lateralization of observational fear learning at the cortical but not thalamic level in mice

Kim

Mátyás

Lee

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Major cognitive and emotional faculties are dominantly lateralized in the human cerebral cortex. The mechanism of this lateralization has remained elusive owing to the inaccessibility of human brains to many experimental manipulations. In this study we demonstrate the hemispheric lateralization of observational fear learning in mice. Using unilateral inactivation as well as electrical stimulation of the anterior cingulate cortex (ACC), we show that observational fear learning is controlled by the right but not the left ACC. In contrast to the cortex, inactivation of either left or right thalamic nuclei, both of which are in reciprocal connection to ACC, induced similar impairment of this behavior. The data suggest that lateralization of negative emotions is an evolutionarily conserved trait and mainly involves cortical operations. Lateralization of the observational fear learning behavior in a rodent model will allow detailed analysis of cortical asymmetry in cognitive functions.social fear | anterograde and retrograde tracing E vidence for hemispheric lateralization exists in various cognitive functions and behaviors in humans (1). In rodents, evidence for cortical lateralization is sparse. Stress-induced neuroendocrine and autonomic responses were shown to be different between left and right medial prefrontal cortex lesions in rats (2, 3). Infantile handling induced increased locomotion in open field tests after right hemisphere lesions (4). In the hippocampus, gene expression profiles (5), receptor expressions (6), and long-term potentiation/long-term depression and innervation patterns (7) displayed certain hemispheric asymmetries. Right and left hemispheric inactivation impaired learning and expression in spatial navigation, respectively (4). Although these data are indicative, evidence for the lateralization of complex emotional behavior is still needed.The processing and expression of negative emotions such as fear display a right hemispheric dominance in humans, as suggested by neuropsychological studies on stroke patients, EEG, and brain functional MRI (8-10). To date, however, the mechanisms that lead to hemispheric asymmetry are largely unknown owing to the obvious limitation in experimental manipulations that can be carried out in human subjects. For example, it is not known whether hemispheric lateralization is a cortical process or is already in place at the subcortical level, driving the hemispheric differences in complex information processing.Fear can be vicariously acquired from social observation of a conspecific's distress (11). This social fear requires the ability to recognize the emotions and feelings of others, suggesting that observational fear is based on empathy (12). In a previous study we had developed a behavioral assay for measuring observational fear learning in mice and found that the anterior cingulate cortex (ACC) is involved in this emotional behavior (13). The ACC has also been implicated in the experience of empathy for pain in humans by brain imaging studies (14). Abnormali...

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Section: Discussionmentioning

confidence: 66%

Lateralization of observational fear learning at the cortical but not thalamic level in mice

Kim

Mátyás

Lee

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Blockade of T-type calcium channels by Ni 2+ (50 μmol/L) disturbs long-term depression in the rat somatosensory cortex [61] and low-threshold calcium spikes in newly generated granule cells in the adult rat hippocampus [62]. Moreover, elevated T-type calcium channel activities in the mediodorsal thalamic nucleus are associated with the impaired fear extinction learning found in phospholipase Cβ4 knockout mice [63]. Therefore, T-type calcium channels may play an important role in memory and cognition.…”

Section: Discussionmentioning

confidence: 99%

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

Noreen¹,

Yabuki²,

Shinoda³

et al. 2018

Pharmacology

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Hypothyroidism is a common disorder that is associated with psychological disturbances such as dementia, depression, and psychomotor disorders. We recently found that chronic treatment with the T-type calcium channel enhancer SAK3 prevents the cholinergic neurodegeneration induced by a single intraperitoneal (i.p.) injection of methimazole (MMI; 75 mg/kg), thereby improving cognition. Here, we evaluated the acute effect of SAK3 on cognitive impairments and its mechanism of action following the induction of hypothyroidism. Hypothyroidism was induced by 2 injections of MMI (75 mg/kg, i.p.) administered once per week. Four weeks after the final MMI treatment, MMI-treated mice showed reduced serum thyroxine (T4) levels and cognitive impairments without depression-like behaviors. Although acute SAK3 (1.0 mg/kg, p.o.) administration failed to ameliorate the decreased T4 levels and histochemical destruction of the glomerular structure, acute SAK3 (1.0 mg/kg, p.o.) administration significantly reduced cognitive impairments in MMI-treated mice. Importantly, the α7 nicotinic acetylcholine receptor (nAChR)-selective inhibitor methyllycaconitine (MLA; 12 mg/kg, i.p.) and T-type calcium channel-specific blocker NNC 55–0396 (25 mg/kg, i.p.) antagonized the acute effect of SAK3 on memory deficits in MMI-treated mice. We also confirmed that acute SAK3 administration does not rescue reduced olfactory marker protein or choline acetyltransferase immunoreactivity levels in the olfactory bulb or medial septum. Taken together, these results suggest that SAK3 has the ability to improve the cognitive decline caused by hypothyroidism directly through activation of nAChR signaling and T-type calcium channels.

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“…An experiment combining genetics, pharmacology, physiology, and microstimulation revealed a role for the MD in extinction learning, especially suggesting that the firing mode of the MD is critical in modulation of fear extinction (Lee et al, 2012). Thalamocortical neurons exhibit two distinct firing modes depending on membrane status: a low voltage-activated T-type Ca 2+ channel-dependent burst of high-frequency action potentials upon hyperpolarization or tonic firing of singular action potentials during depolarization (Llinas and Jahnsen, 1982;Sherman, 2001).…”

Section: Mediodorsal Thalamic Nucleus In Fear Extinctionmentioning

confidence: 99%

“…These results suggest that an increase of tonic firing in the MD is necessary for fear extinction. In contrast to the role of tonic firing, electrical microstimulation with a protocol mimicking burst spikes in the MD suppresses fear extinction (Lee et al, 2012) (PLCβ4), which is physiologically coupled with mGluR1, were strongly impaired in acquisition of extinction. MDspecific knockdown of PLCβ4 leads to similar impairment in extinction.…”

Section: Mediodorsal Thalamic Nucleus In Fear Extinctionmentioning

confidence: 99%

The role of mediodorsal thalamic nucleus in fear extinction

Lee

Shin

2016

J Anal Sci Technol

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Understanding the neural mechanism underlying the formation and extinction of fear memory would guide the development of advanced strategies for treatment of post-traumatic stress disorder (PTSD), a generalized anxiety disorder. The mediodorsal thalamic nucleus (MD) is reciprocally connected with limbic circuitry including the prefrontal cortex and amygdala, key structures for fear formation, and extinction. In addition to the distinctive anatomical relationships, the MD participates in learning and memory process in fear extinction through thalamic dual firing modes: tonic and burst. This review will briefly describe neural mechanisms of fear extinction and highlight the role of MD in modulation of fear extinction. We suggest that excitability of the MD neurons may modulate fear circuits and can be a novel target for treatment of anxiety disorders.

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Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice

Cited by 77 publications

References 45 publications

Lateralization of observational fear learning at the cortical but not thalamic level in mice

Lateralization of observational fear learning at the cortical but not thalamic level in mice

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

The role of mediodorsal thalamic nucleus in fear extinction

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