Effects of ß-Hydroxy ß-Methylbutyrate Supplementation on Working Memory and Hippocampal Long-Term Potentiation in Rodents.

ß-hydroxy ß-methylbutyrate (HMB), a metabolite of the essential amino acid leucine, has been shown to preserve muscle mass and strength during aging. The signaling mechanism by which HMB elicits its favorable effects on protein metabolism in skeletal muscle is also preserved in the brain. However, there are only a few studies, all at relatively high doses, addressing the effect of HMB supplementation on cognition. This study evaluated the effects of different doses of HMB on the potentiation of hippocampal synapses following the experimental induction of long-term potentiation (LTP) in the hippocampus of behaving rats, as well as on working memory test (delayed matching-to-position, DMTP) in mice. HMB doses in rats were 225 (low), 450 (medium), and 900 (high) mg/kg body weight/day and were double in mice. Rats who received medium or high HMB doses improved LTP, suggesting that HMB administration enhances mechanisms related to neuronal plasticity. In the DMTP test, mice that received any of the tested doses of HMB performed better than the control group in the overall test with particularities depending on the dose and the task phase.

Optic nerve and retinal electrostimulation in rats: direct activation of the retinal ganglion cells.

Visual prosthesis is competing with biological approaches to restore vision to the blind. Understanding and developing the ability to replicate the neural code of the retina are key factors that can bring bionic vision significant advantage. Here, electrically evoked potentials were recorded in anesthetized rats from the dorsal surface of the superior colliculus. Electrical stimuli of different amplitudes were delivered at the retina and the optic nerve. An evoked potential appeared in both cases within the first 5 ms post-stimulus suggesting that this component of the response was initiated by direct activation of the retinal ganglion cells. However, in the case of retinal neurostimulation, a second evoked potential occurred $9.0 \pm 3.4$ ms after the stimulus delivery. Because this component was not present in the case of optic nerve electrostimulation, it is expected to be originated by the activation of other cells in the retinal network.

Sialic Acid and Sialylated Oligosaccharide Supplementation during Lactation Improves Learning and Memory in Rats.

Sialic acids (Sia) are postulated to improve cognitive abilities. This study evaluated Sia effects on rat behavior when administered in a free form as N-acetylneuraminic acid (Neu5Ac) or conjugated as 6'-sialyllactose (6'-SL). Rat milk contains Sia, which peaks at Postnatal Day 9 and drops to a minimum by Day 15. To bypass this Sia peak, a cohort of foster mothers was used to raise the experimental pups. A group of pups received a daily oral supplementation of Neu5Ac to mimic the amount naturally present in rat milk, and another group received the same molar amount of Sia as 6'-SL. The control group received water. After weaning, rats were submitted to behavioral evaluation. One year later, behavior was re-evaluated, and in vivo long-term potentiation (LTP) was performed. Brain samples were collected and analyzed at both ages. Adult rats who received Sia performed significantly better in the behavioral assessment and showed an enhanced LTP compared to controls. Within Sia groups, 6'-SL rats showed better scores in some cognitive outcomes compared to Neu5Ac rats. At weaning, an effect on polysialylated-neural cell adhesion molecule (PSA-NCAM) levels in the frontal cortex was only observed in 6'-SL fed rats. Providing Sia during lactation, especially as 6'-SL, improves memory and LTP in adult rats.

Chaotic and Fast Audiovisuals Increase Attentional Scope but Decrease Conscious Processing.

Audiovisual cuts involve spatial, temporal, and action narrative leaps. They can even change the meaning of the narrative through film editing. Many cuts are not consciously perceived, others are, just as we perceive or not the changes in real events. In this paper, we analyze the effects of cuts and different editing styles on 36 subjects, using electroencephalographic (EEG) techniques and the projection of stimuli with different audiovisual style of edition but the same narrative. Eyeblinks, event-related potentials (ERPs), EEG spectral power and disturbances, and the functional and effective connectivity before and after the cuts were analyzed. Cuts decreased blink frequency in the first second following them. Cuts also caused an increase of the alpha rhythm, with a cortical evolution from visual toward rostral areas. There were marked differences between a video-clip editing style, with greater activities evoked in visual areas, and the classic continuous style of editing, which presented greater activities in the frontal zones. This was reflected by differences in the theta rhythm between 200 and 400 ms, in visual and frontal zones, and can be connected to the different demands that each style of edition makes on working memory and conscious processing after cutting. Also, at the time of cuts, the causality between visual, somatosensory, and frontal networks is altered in any editing style. Our findings suggest that cuts affect media perception and chaotic and fast audiovisuals increase attentional scope but decrease conscious processing.

The Motor Cortex Is Involved in the Generation of Classically Conditioned Eyelid Responses in Behaving Rabbits.

UNLABELLED: Classical blink conditioning is a well known model for studying neural generation of acquired motor responses. The acquisition of this type of associative learning has been related to many cortical, subcortical, and cerebellar structures. However, until now, no one has studied the motor cortex (MC) and its possible role in classical eyeblink conditioning. We recorded in rabbits the activity of MC neurons during blink conditioning using a delay paradigm. Neurons were identified by their antidromic activation from facial nucleus (FN) or red nucleus (RN). For conditioning, we used a tone as a conditioned stimulus (CS) followed by an air puff as an unconditioned stimulus (US) that coterminated with it. Conditioned responses (CRs) were determined from the electromyographic activity of the orbicularis oculi muscle and/or from eyelid position recorded with the search coil technique. Type A neurons increased their discharge rates across conditioning sessions and reached peak firing during the CS-US interval, while type B cells presented a second peak during US presentation. Both of them project to the FN. Type C cells increased their firing across the CS-US interval, reaching peak values at the time of US presentation, and were activated from the RN. These three types of neurons fired well in advance of the beginning of CRs and changed with them. Reversible inactivation of the MC during conditioning evoked a decrease in learning curves and in the amplitude of CRs, while train stimulation of the MC simulated the profile and kinematics of conditioned blinks. In conclusion, MC neurons are involved in the acquisition and expression of CRs. SIGNIFICANCE STATEMENT: Classical blink conditioning is a popular experimental model for studying neural mechanisms underlying the acquisition of motor skills. The acquisition of this type of associative learning has been related to many cortical, subcortical, and cerebellar structures. However, until now, no one has studied the motor cortex (MC) and its possible role in classical eyeblink conditioning. Here, we report that the firing activities of MC neurons, recorded in behaving rabbits, are related to and preceded the initiation of conditioned blinks. MC neurons were identified as projecting to the red or facial nuclei and encoded the kinematics of conditioned eyelid responses. The timed stimulation of recording sites simulated the profile of conditioned blinks. MC neurons play a role in the acquisition and expression of these acquired motor responses.

Physical exercise protects against Alzheimer's disease in 3xTg-AD mice.

Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer's disease (AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage(7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg-AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg-AD mouse further support the value of this healthy life-style against neurodegeneration.

Effects of thyroid hormone replacement on associative learning and hippocampal synaptic plasticity in adult hypothyroid rats.

Activity-dependent changes taking place at the hippocampal perforant pathway-dentate gyrus synapse during classical eyeblink conditioning were recorded in adult thyroidectomized (hypothyroid) and control (euthyroid) rats, and in animals treated with thyroid hormones 20 days after thyroidectomy (recovery rats). The aim was to determine the contribution of thyroid hormones and the consequences of adult-onset hypothyroidism to both associative learning and the physiological potentiation of hippocampal synapses during the actual learning process in alert behaving animals. Control and recovery rats presented similar learning curves, whereas hypothyroid animals presented lower values. A single pulse presented to the perforant pathway during the conditioned-unconditioned inter-stimulus interval evoked a monosynaptic field excitatory postsynaptic potential in dentate granule cells (whose slope was linearly related to the rate of acquisition in the control group), but not in hypothyroid and recovery animals. Input-output relationships and long-term potentiation evoked by train stimulation of the perforant pathway were significantly depressed in hypothyroid animals. Thyroid hormone treatment failed to normalize these two neurophysiological abnormalities observed in hypothyroid animals. In contrast, paired-pulse facilitation was not affected by thyroidectomy. The results indicate that thyroid hormone treatment after a short period of adult hypothyroidism helps to restore some hippocampally dependent functions, such as classical conditioning, but not other hippocampal properties, such as the synaptic plasticity evoked during associative learning and during experimentally induced long-term potentiation. The present results have important clinical implications for the handling of patients with adult-onset thyroid diseases.

Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice.

One of the brain sites more directly related with learning and memory processes is the hippocampus. We recorded, in conscious mice, the activity-dependent changes taking place at the hippocampal CA3-CA1 synapse during the acquisition, extinction, recall, and reconditioning of an associative task. Mice were classically conditioned to evoke eyelid responses using a trace [conditioned stimuli (CS), tone; unconditioned stimuli (US), shock] paradigm. A single electrical pulse presented to the Schaffer collateral-commissural pathway during the CS-US interval evoked a monosynaptic field EPSP (fEPSP) at ipsilateral CA1 pyramidal cells. The slope of evoked fEPSPs increased across conditioning sessions and decreased during extinction, being linearly related to learning evolution. In contrast, fEPSPs were not modified when evoked in control mice in the absence of a conditioning protocol. Long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals prevented acquisition, extinction, recall, or reconditioning, depending on the moment when it was triggered. Learning and memory impairments evoked by LTP induction resulted probably from the functional saturation of the CA3-CA1 synapse, although an additional disturbance of the subsequent information transfer toward postsynaptic circuits cannot be discarded. CGP 39551 [(E)-(+/-)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester] (an NMDA antagonist) prevented LTP induction in behaving mice, as well as the acquisition of an eyelid learned response, and the synaptic changes taking place at the CA3-CA1 synapse across conditioning. In conclusion, the responsivity of the CA3-CA1 synapse seems to be modulated during associative learning, and both processes are prevented by experimental LTP or NMDA-receptor inactivation. Our results provide evidence of a relationship between activity-dependent synaptic plasticity and associative learning in behaving mice.

Gradient of adaptability in four different motor systems performing the same learned motor task in cats.

The ability of four different brainstem motoneuron pools to perform a newly acquired motor task was studied in alert cats. A classical conditioning of eyelid responses was carried out in (i). unoperated animals, and in animals with (ii). transection, 180 degrees rotation, and re-suture of the zygomatic facial nerve branch, (iii). a crossed anastomosis of the buccal to the zygomatic facial nerve branch and (iv). a hypoglossal-facial nerve anastomosis. Animals were conditioned with a delay paradigm using a tone (350 ms, 600 Hz, 90 dB) as conditioned stimulus, followed 250 ms later by an air puff (100 ms, 3 kg/cm2) as unconditioned stimulus. Animals with zygomatic nerve rotation performed conditioned responses (CRs) at control rate, with significantly larger amplitude, area and velocity, but a de-synchronized oscillatory pattern. Animals with buccal-zygomatic anastomosis acquired CRs at control rate, but these CRs had significantly smaller amplitude than those of controls and a de-synchronized pattern. Animals with a hypoglossal-facial anastomosis were unable to perform CRs. The trigeminal hyper-reflexia triggered by the axotomy was probably the origin of the large CRs after zygomatic nerve rotation. Trigeminal hyper-reflexia could also contribute to generation of the small CRs recorded after buccal-zygomatic anastomosis. Although trigeminal hyper-reflexia was also present following hypoglossal-facial anastomosis, hypoglossal motoneurons did not reach their firing threshold to perform CRs. In accordance with the embryonic origin of involved motoneurons, animals with buccal-zygomatic and hypoglossal-facial anastomoses moved the ipsilateral eyelid synchronously to mouth-related activities. It is suggested that there is a gradient of adaptability in motoneuron pools forced to perform new motor tasks through foreign muscles, which depends on their embryological origins and functional properties.