Spatiotemporal organization and thalamic modulation of seizures in the mouse medial thalamic-anterior cingulate slice

Abstract

SUMMARYPurpose: Seizure-like activities generated in anterior cingulate cortex (ACC) are usually classified as simple partial and are associated with changes in autonomic function, motivation, and thought. Previous studies have shown that thalamic inputs can modulate ACC seizure, but the exact mechanisms have not been studied thoroughly. Therefore, we investigated the role of thalamic inputs in modulating ACC seizure-like activities. In addition, seizure onset and propagation are difficult to determine in vivo in ACC. We studied the spatiotemporal changes in epileptiform activity in this cortex in a thalamic-ACC slice to clearly determine seizure onset. Methods: We used multielectrode array (MEA) recording and calcium imaging to investigate the modulatory effect of thalamic inputs in a thalamic-ACC slice preparation. Key Findings: Seizure-like activities induced with 4-aminopyridine (4-AP; 250 lM) and bicuculline (5-50 lM) in ACC were attenuated by glutamate receptor antagonists, and the degree of disinhibition varied with the dose of bicuculline. Seizure-like activities were decreased with 1 Hz thalamic stimulation, whereas corpus callosum stimulation could increase ictal discharges. Amplitude and duration of cingulate seizure-like activities were augmented after removing thalamic inputs, and this effect was not observed with those induced with elevated bicuculline (50 lM). Seizure-like activities were initiated in layers II/III and, after thalamic lesions, they occurred mainly in layers V/VI. Two-dimensional current-source density analyses revealed sink signals more frequently in layers V/VI after thalamic lesions, indicating that these layers produce larger excitatory synchronization. Calcium transients were synchronized after thalamic lesions suggesting that ACC seizure-like activities are subjected to desynchronizing modulation by thalamic inputs. Therefore, ACC seizure-like activities are subject to desynchronizing modulation from medial thalamic inputs to deep layer pyramidal neurons. Significance: Cingulate seizure-like activities were modulated significantly by thalamic inputs. Repeated stimulation of the thalamus efficiently inhibited epileptiform activity, demonstrating that the desynchronization was pathway-specific. The clinical implications of deep thalamic stimulation in the modulation of cingulate epileptic activity require further investigation.

Mild systemic inflammation and moderate hypoxia transiently alter neuronal excitability in mouse somatosensory cortex

“…The amplitudes of the EEs match values from studies in which similar methods were used to discriminate EEs (Chang et al, 2011), confirming the validity of our method. The lower stimulation thresholds needed to evoke epileptiform activity in all treated animals suggest a more sensitive and thus more excitable neuronal network.…”

“…Spike datasets from all electrodes were imported into Matlab 7.7 (Mathworks, Natick, MA, USA) for analysis using a custom written routine. To be classified as an epileptiform event, a burst needed to last more than 200 ms and had to be detected on at least two neighboring cortical columns of at least 3 different electrodes monitoring activity in neocortical layers 2/3, 4, 5 and 6 (Chang et al, 2011). …”

Treatment with direct-current stimulation against cingulate seizure-like activity induced by 4-aminopyridine and bicuculline in an in vitro mouse model

“…In in vivo studies, the amounts of current passing through a particular brain region are difficult to measure, and also have some non-specific effects such as alteration on vascular activities. Therefore, in the present study, we used an in vitro brain slice preparation that was developed previously (Lee et al, 2007;Chang et al, 2011 to uncover the underlying mechanism of the effect of DCS on synaptic plasticity and seizure-like activity threshold. Thus, the present study investigated the long-term effects of polarizing field on ACC seizure-like activities.…”

Temporal and spatial dynamics of thalamus-evoked activity in the anterior cingulate cortex

“…Importantly, the spatiotemporal profiles and constructed trajectory paths persisted and could be clearly defined and distributed in the cortical layers stimulated at different medial thalamic sites in the same slice. Thus, this activation pattern provided a useful model for further investigation of the mechanisms that underlie the alterations of circuit function under normal physiological or pathological conditions, such as induced seizure activity in vitro (Chang et al, 2011). The stimulation employed for MT stimulation was low, and the effective stimulation sites were restricted to the MT region, consistent with our previous test of the range of current spread (Kung and Shyu, 2002).…”

“…GABAergic innervation of layer V corticothalamic neurons has also been observed (Kuroda et al, 2004). Our recent study showed that the GABA A receptor antagonist bicuculline induced long-lasting seizure-like activity in the ACC that could be modulated by thalamic inputs via GABAergic interneurons (Chang et al, 2011). These findings suggest that this positive component is a summation of dendritic hyperpolarization when GABAergic interneurons are excited in a feedback fashion either by antidromic or orthodromic stimulation.…”