RESUMEN

Autophagy is a lysosomal degradation pathway that regulates cellular homeostasis. It is constitutively active in neurons and controls the essential steps of neuronal development, leading to its dysfunction in neurodevelopmental disorders. Although mTOR-associated impaired autophagy has previously been reported in neurodevelopmental disorders, there is lack of information about the dysregulation of mTOR-independent autophagy in neurodevelopmental disorders. In this study, we investigated whether the loss of Epac2, involved in the mTOR-independent pathway, affects autophagy activity and whether the activity of autophagy is associated with social-behavioral phenotypes in mice with Epac2 deficiencies. We observed an accumulation of autophagosomes and a significant increase in autophagic flux in Epac2-deficient neurons, which had no effect on mTOR activity. Next, we examined whether an increase in autophagic activity contributed to the social behavior exhibited in Epac2-/- mice. The social recognition deficit observed in Epac2-/- mice recovered in double transgenic Epac2-/-: Atg5+/- mice. Our study suggests that excessive autophagy due to Epac2 deficiencies may contribute to social recognition defects through an mTOR-independent pathway.

Asunto(s)

RESUMEN

Successfully navigating dynamic environments requires balancing the decision to stay at an optimal choice with that to switch to an alternative to acquire new knowledge. However, the genetic factors and cellular activity shaping this "stay or switch" action decision remains largely unidentified. Here we find that mice carrying a deletion of the exchange protein directly activated by cAMP 2 (Epac2) gene, a putative autism locus, exhibit perseverative "stay" behavior in a dynamic foraging task. Anatomical analysis found that the loss of Epac2 resulted in a significant decrease in the density of PV-expressing interneurons in the ventrolateral orbitofrontal cortex (OFC) and dorsal striatum (dSTR). Further, in vitro whole cell patch clamp recordings of PV+ GABAergic interneurons in the dSTR revealed altered neural activity in Epac2 KO mice in response to dopamine. Our findings highlight a potential role of Epac2 in structural changes and neural responses of PV-expressing GABAergic interneurons in the ventrolateral OFC and dSTR during value-based reinforcement learning and link Epac2 function to abnormal decision-making processes and perseverative behaviors seen in autism.

Asunto(s)

RESUMEN

OBJECTIVE: Brain activity is known to be voluntarily controllable by neurofeedback, a kind of electroencephalographic (EEG) operant conditioning. Although its efficacy in clinical effects has been reported, it is yet to be uncovered whether or how a specific band activity is controllable. Here, we examined EEG spectral profiles along with conditioning training of a specific brain activity, theta band (4-8 Hz) amplitude, in rats. METHODS: During training, the experimental group received electrical stimulation to the medial forebrain bundle contingent to suppression of theta activity, while the control group received stimulation non-contingent to its own band activity. RESULTS: In the experimental group, theta activity gradually decreased within the training session, while there was an increase of theta activity in the control group. There was a significant difference in theta activity during the sessions between the two groups. The spectral theta peak, originally located at 7 Hz, shifted further towards higher frequencies in the experimental group. CONCLUSION: Our results showed that an operant conditioning technique could train rats to control their specific EEG activity indirectly, and it may be used as an animal model for studying how neuronal systems work in human neurofeedback.

RESUMEN

Head fixation is a technique of immobilizing animal's head by attaching a head-post on the skull for rigid clamping. Traditional head fixation requires surgical attachment of metallic frames on the skull. The attached frames are then clamped to a stationary platform resulting in immobilization of the head. However, metallic frames for head fixation have been technically difficult to design and implement in general laboratory environment. In this study, we provide a novel head fixation method. Using a custom-made head fixation bar, head mounter is constructed during implantation surgery. After the application of acrylic resin for affixing implants such as electrodes and cannula on the skull, additional resins applied on top of that to build a mold matching to the port of the fixation bar. The molded head mounter serves as a guide rails, investigators conveniently fixate the animal's head by inserting the head mounter into the port of the fixation bar. This method could be easily applicable if implantation surgery using dental acrylics is necessary and might be useful for laboratories that cannot easily fabricate CNC machined metal head-posts.

Asunto(s)

RESUMEN

BACKGROUND: To investigate the relationship between neural function and behavior it is necessary to record neuronal activity in the brains of freely behaving animals, a technique that typically involves tethering to a data acquisition system. Optimally this approach allows animals to behave without any interference of movement or task performance. Currently many laboratories in the cognitive and behavioral neuroscience fields employ commercial motorized commutator systems using torque sensors to detect tether movement induced by the trajectory behaviors of animals. RESULTS: In this study we describe a novel motorized commutator system which is automatically controlled by video tracking. To obtain accurate head direction data two light emitting diodes were used and video image noise was minimized by physical light source manipulation. The system calculates the rotation of the animal across a single trial by processing head direction data and the software, which calibrates the motor rotation angle, subsequently generates voltage pulses to actively untwist the tether. This system successfully provides a tether twist-free environment for animals performing behavioral tasks and simultaneous neural activity recording. CONCLUSIONS: To the best of our knowledge, it is the first to utilize video tracking generated head direction to detect tether twisting and compensate with a motorized commutator system. Our automatic commutator control system promises an affordable and accessible method to improve behavioral neurophysiology experiments, particularly in mice.

Asunto(s)

RESUMEN

Head restraining is an experimental technique that firmly secures the animal's head to a fixation apparatus for the precise control and sensing of behaviors. However, procedural and surgical difficulties and limitations have been obstructing the use of the technique in neurophysiological and behavioral experiments. Here, we propose a novel design of the head-restraining apparatus which is easy to develop and convenient for practical use. Head restraining procedure can be completed by sliding the head mounter, which is molded by dental cement during implantation surgery, into the port, which serves as matching guide rails for the mounter, of the fixation bar. So neither skull-attached plates nor screws for fixation are needed. We performed intracranial self stimulation experiment in rats using the newly designed device. Rats were habituated to acclimatize the head-restraint environment and trained to discriminate two spatially distinguished cues using a customized push-pull lever as an operandum. Direct electrical stimulation into the medial forebrain bundle served as reward. We confirmed that head restraining was stable throughout experiments and rats were able to learn to manipulate the lever after successful habituation. Our experimental framework might help precise control or sensing of behavior under head fixed rats using direct electrical brain stimulation as a reward.

RESUMEN

We studied the effects of acetylcholinesterase inhibitors, donepezil and galantamine, and an N-methyl-D-aspartate (NMDA) receptor blocker, memantine, on sleep-wake architecture in rats. Screw electrodes were chronically implanted into the frontal and parietal cortex for the electroencephalography (EEG). EEG was recorded with a bio-potential amplifier for 8 h from 09:30 to 17:30. Vibration was recorded to monitor animal activity with a vibration measuring device. Sleep-wake states such as wake (W), slow-wave sleep (S) and paradoxical or rapid eye movement sleep (P), were scored every 10 sec by an experimenter. We measured mean episode duration and number of episode to determine which factor sleep disturbance was attributed to. Donepezil and memantine showed a significant increase in total W duration and decreases in total S and P duration and delta activity. Memantine showed increases in sleep latency and motor activity. Changes of S and P duration in memantine were attributed from changes of mean episode duration. Galantamine had little effect on sleep architecture. From these results, it is showed that galantamine may be an anti-dementia drug that does not cause sleep disturbances and memantine may be a drug that causes severe sleep disturbance.

RESUMEN

Although quantitative EEG parameters, such as spectral band powers, are sensitive to centrally acting drugs in dose- and time-related manners, changes of the EEG parameters are redundant. It is desirable to reduce multiple EEG parameters to a few components that can be manageable in a real space as well as be considered as parameters representing drug effects. We calculated factor loadings from normalized values of eight relative band powers (powers of 0.5, 1.0~2.0, 2.5~4.0, 4.5~5.5, 6.0~8.0, 8.5~12.0, 12.5~24.5, and 25~49.5 Hz bands expressed as ratios of the power of 0.5-49.5 Hz band) of EEG during pre-drug periods (11:00~12:00) by factor analysis and constructed a two-dimensional canonical space (reference canonical space) by canonical correlation analysis. Eight relative band powers of EEG produced by either physostigmine or yohimbine were reduced to two canonical scores in the reference canonical space. While changes of the band powers produced by physostigmine and yohimbine were too redundant to describe the difference between two drugs, locations of two drugs in the reference canonical space represented the difference between two drug's effects on EEG. Because the distance between two locations in the canonical space (Mahalanobis distance) indicates the magnitude of difference between two different sets of EEG parameters statistically, the canonical scores and the distance may be used to quantitatively and qualitatively describe the dose-dependent and time-dependent effects and also tell similarity and dissimilarity among effects. Then, the combination of power spectral analysis and statistical analysis may help to classify actions of centrally acting drugs.