Exp Neurobiol 2015; 24(2): 126-132
Published online June 30, 2015
© The Korean Society for Brain and Neural Sciences
1Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, 2Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
Correspondence to: *To whom correspondence should be addressed.
TEL: 82-53-660-6861, FAX: 82-53-426-7731
Cross-talk between the thalamus and cortex has been implicated in attention but its pathogenic role in attention-deficit/hyperactivity disorder (ADHD) remains unknown. Here, I demonstrate that
Keywords: ADHD, GIT1, Thalamic oscillation, Coherence
Among overwhelming amount of sensory signals from all sensory organs, brain selectively processes relevant sensory information at the expense of others. This process of allocating limited processing resources to relevant information is referred to as attention, which has been the focus of various studies because of its importance in human cognition. Thalamus is a brain region that relays sensory and motor information to the cortex and regulates cognitive processes including consciousness, attention, wakefulness, and sleep [1,2,3,4,5,6,7]. Cross-talk between the thalamus and the cortex has been implicated in attention since all sensory information is relayed to the cortex via thalamus .
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder that affects 5~10% of school-age children worldwide and frequently persists into adulthood . Because of its high prevalence and lifelong impairment, massive researches have been conducted to delineate neural correlates of the disorder. Though several lines of evidences imply the association between abnormalities in thalamus and ADHD [10,11,12], the pathogenic role of the thalamus in ADHD is still elusive.
GIT1 (G protein-coupled receptor kinase-interacting protein-1) is a multifunctional signaling adaptor associated with ADHD .
Here, I report that the thalamus of
Amphetamine (U.S. Pharmacopia) and ethosuximide (Tokyo Chemical Industry) were dissolved in 0.9% saline and distilled water to final concentrations of 1.2 g/L and 60 g/L, respectively. Solutions for injection were filtered with Minisart filter (0.2 µm; Sartorius Stedim Biotech). WT and
Mice were anesthetized by ketamine (Yuhan Corporation). For depth recording, a parylene-coated tungsten electrode (0.005 in, 2 MΩ, A-M Systems, Inc.) was implanted into the ventrobasal or mediodorsal nucleus of the thalamus with grounding electrodes over the cerebellum. LFP recordings were performed 1 week after the implantation. LFP activities (sampled at 200 Hz) of freely moving mice were recorded for 1 h using the NACGather program (Theta Burst Corp.). Amphetamine was delivered intraperitoneally to mice 20 min after basal LFP recording. LFP activity was recorded for 1 h briefly after the injection. LFP recordings were analyzed by Matlab, using EEGLAB and custom-written coding.
The size of the open field box was 40×40×40 cm, and the center zone line was located 6.5 cm apart from the edge. Mice were placed in the center of the chamber in the beginning of the assay, and spontaneous locomotion activity was observed and recorded for 60 min in an open field chamber, briefly after injection. The results were analyzed by Ethovision 3.1 program (Noldus). The total distance moved was obtained by summing the movements made during 10~60 min. All behavioral assays were performed in a blind manner.
The apparatus used in the open field tests was used for object recognition tests. During the sample phase, mice were allowed to explore two identical objects for 10 min. Objects were put in the center of the chamber, and mice were first put in the chamber facing the wall. Exploration time for each object was measured. In the test phase, performed 24 h later, one of the two objects was replaced with a new one, and exploration time for each object was measured. All objects were pre-tested to confirm that there was no difference in object preference using C57BL/6 wild-type mice and C57BL/6-129/SV/Jae hybrid wild-type mice.
As previous studies have identified close connection between ventrobasal thalamus and prefrontal cortex during attention task [15,16], I hypothesized that abnormal theta oscillation in the PFC of
Thus, I examined the functional properties of the ventrobasal thalamus of
Abnormal theta rhythms in the human cortex are thought to be coupled with those in the thalamus through the thalamocortical pathway, a process that has been termed thalamocortical dysrhythmia (TCD) . To this end, I simultaneously measured cortical EEG rhythms and thalamic activities (LFP) in WT and
Increased coherence between the
Inhibitory inputs into the thalamus facilitate hyperpolarization of thalamic neurons, which is required for the recovery of T-type calcium channels from inactivation and low-threshold spikes generation. The latter is a neuronal burst activity closely related to thalamic rhythms that are conveyed to other brain regions, including cortex . Ethosuximide, which is mainly used as an antiepileptic agent, is a well-known T-type calcium channel blocker and suppressant of thalamic bursts . Here, I tested whether ethosuximide could suppress 3-Hz rhythms in the
Similar to the effects of amphetamine, ethosuximide normalized 3-Hz thalamic rhythms in
Unlike the reported rescue of novel-object recognition memory in
I herein provide evidence suggesting that enhanced 3-Hz rhythms in the thalamus may contribute to enhanced cortical theta EEG rhythms and hyperactivity in
The 3-Hz rhythms in the
The circuit-level mechanism for enhanced 3-Hz rhythms in the thalamus of
Another source of inhibitory inputs to the thalamus comes from endopeduncular nucleus (analogous to the internal globus pallidus in primates), which is negatively regulated by the globus pallidus directly or indirectly via subthalamic nucleus [26,27]. Inhibitory projections from the endopeduncular nucleus to the thalamus significantly influence firing rates and rhythmic activities of the ventrolateral and intralaminar thalamic nuclei . Globus pallidus also modulates thalamus via its direct and inhibitory modulation of TRN neurons . Amphetamine may indirectly regulate GABAergic neurons, as psychostimulants suppress the stimulatory action of the locus coeruleus onto the TRN .
Finally, I found that ethosuximide failed to restore novel object recognition while correcting hyperactivity in
In summary, my data indicate that 3-Hz thalamic rhythms are associated with cortical theta EEG rhythms and hyperactivity in