Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice.

BACKGROUND: As one major symptom of Alzheimer's disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. METHODS: mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK-/-) mice. Animals' cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. RESULTS: Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK-/- mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. CONCLUSIONS: Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.

Dark exposure reduces high-frequency hearing loss in C57BL/6J mice.

Plastic changes in the brain are primarily limited to early postnatal periods. Recovery of adult brain plasticity is critical for the effective development of therapies. A brief (1-2 week) duration of visual deprivation (dark exposure, DE) in adult mice can trigger functional plasticity of thalamocortical and intracortical circuits in the primary auditory cortex suggesting improved sound processing. We tested if DE enhances the ability of adult mice to detect sounds. We trained and continuously evaluated the behavioral performance of mice in control and DE conditions using automated home-cage training. Consistent with age-related peripheral hearing loss present in C57BL/6J mice, we observed decreased performance for high-frequency sounds with age, which was reduced by DE. In CBA mice with preserved peripheral hearing, we also found that DE enhanced auditory performance in low and mid frequencies over time compared to the control.

Auditory discrimination learning differentially modulates neural representation in auditory cortex subregions and inter-areal connectivity.

Changes in sound-evoked responses in the auditory cortex (ACtx) occur during learning, but how learning alters neural responses in different ACtx subregions and changes their interactions is unclear. To address these questions, we developed an automated training and widefield imaging system to longitudinally track the neural activity of all mouse ACtx subregions during a tone discrimination task. We find that responses in primary ACtx are highly informative of learned stimuli and behavioral outcomes throughout training. In contrast, representations of behavioral outcomes in the dorsal posterior auditory field, learned stimuli in the dorsal anterior auditory field, and inter-regional correlations between primary and higher-order areas are enhanced with training. Moreover, ACtx response changes vary between stimuli, and such differences display lag synchronization with the learning rate. These results indicate that learning alters functional connections between ACtx subregions, inducing region-specific modulations by propagating behavioral information from primary to higher-order areas.

Trial-by-trial variability in cortical responses exhibits scaling of spatial correlations predicted from critical dynamics.

In the mammalian cortex, even simple sensory inputs or movements activate many neurons, with each neuron responding variably to repeated stimuli-a phenomenon known as trial-by-trial variability. Understanding the spatial patterns and dynamics of this variability is challenging. Using cellular 2-photon imaging, we study visual and auditory responses in the primary cortices of awake mice. We focus on how individual neurons' responses differed from the overall population. We find consistent spatial correlations in these differences that are unique to each trial and linearly scale with the cortical area observed, a characteristic of critical dynamics as confirmed in our neuronal simulations. Using chronic multi-electrode recordings, we observe similar scaling in the prefrontal and premotor cortex of non-human primates during self-initiated and visually cued motor tasks. These results suggest that trial-by-trial variability, rather than being random noise, reflects a critical, fluctuation-dominated state in the cortex, supporting the brain's efficiency in processing information.

Visually or auditorily induced seizures involve the activation of nonhippocampal brain areas and hippocampal removal does not alleviate seizures in a mouse model of temporal lobe epilepsy.

OBJECTIVE: Several studies have attributed epileptic activities in temporal lobe epilepsy (TLE) to the hippocampus; however, the participation of nonhippocampal neuronal networks in the development of TLE is often neglected. Here, we sought to understand how these nonhippocampal networks are involved in the pathology that is associated with TLE disease. METHODS: A kainic acid (KA) model of temporal lobe epilepsy was induced by injecting KA into dorsal hippocampus of C57BL/6J mice. Network activation after spontaneous seizure was assessed using c-Fos expression. Protocols to induce seizure using visual or auditory stimulation were developed, and seizure onset zone (SOZ) and frequency of epileptic spikes were evaluated using electrophysiology. The hippocampus was removed to assess seizure recurrence in the absence of hippocampus. RESULTS: Our results showed that cortical and hippocampal epileptic networks are activated during spontaneous seizures. Perturbation of these networks using visual or auditory stimulation readily precipitates seizures in TLE mice; the frequency of the light-induced or noise-induced seizures depends on the induction modality adopted during the induction period. Localization of SOZ revealed the existence of cortical and hippocampal SOZ in light-induced and noise-induced seizures, and the development of local and remote epileptic spikes in TLE occurs during the early stage of the disease. Importantly, we further discovered that removal of the hippocampi does not stop seizure activities in TLE mice, revealing that seizures in TLE mice can occur independent of the hippocampus. SIGNIFICANCE: This study has shown that the network pathology that evolves in TLE is not localized to the hippocampus; rather, remote brain areas are also recruited. The occurrence of light-induced or noise-induced seizures and epileptic discharges in epileptic mice is a consequence of the activation of nonhippocampal brain areas. This work therefore demonstrates the fundamental role of nonhippocampal epileptic networks in generating epileptic activities with or without the hippocampus in TLE disease.

Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses.

The hippocampus is broadly impacted by neuromodulations. However, how neuropeptides shape the function of the hippocampus and the related spatial learning and memory remains unclear. Here, we discover the crucial role of cholecystokinin (CCK) in heterosynaptic neuromodulation from the medial entorhinal cortex (MEC) to the hippocampus. Systematic knockout of the CCK gene impairs CA3-CA1 LTP and space-related performance. The MEC provides most of the CCK-positive neurons projecting to the hippocampal region, which potentiates CA3-CA1 long-term plasticity heterosynaptically in a frequency- and NMDA receptor (NMDAR)-dependent manner. Selective inhibition of MEC CCKergic neurons or downregulation of their CCK mRNA levels also impairs CA3-CA1 LTP formation and animals' performance in the water maze. This excitatory extrahippocampal projection releases CCK upon high-frequency excitation and is active during animal exploration. Our results reveal the critical role of entorhinal CCKergic projections in bridging intra- and extrahippocampal circuitry at electrophysiological and behavioral levels.

Visuoauditory Associative Memory Established with Cholecystokinin Under Anesthesia Is Retrieved in Behavioral Contexts.

Plastic change in neuronal connectivity is the foundation of memory encoding. It is not clear whether the changes during anesthesia can alter subsequent behavior. Here, we demonstrated that in male rodents under anesthesia, a visual stimulus (VS) was associated with electrical stimulation of the auditory cortex or natural auditory stimulus in the presence of cholecystokinin (CCK), which guided the animals' behavior in a two-choice auditory task. Auditory neurons became responsive to the VS after the pairings. Moreover, high-frequency stimulation of axon terminals of entorhinal CCK neurons in the auditory cortex enabled LTP of the visual response in the auditory cortex. Such pairing during anesthesia also generated VS-induced freezing in an auditory fear conditioning task. Finally, we verified that direct inputs from the entorhinal CCK neurons and the visual cortex enabled the above neural plasticity in the auditory cortex. Our findings suggest that CCK-enabled visuoauditory association during anesthesia can be translated to the subsequent behavior action.SIGNIFICANCE STATEMENT Our study provides strong evidence for the hypothesis that cholecystokinin plays an essential role in the formation of cross-modal associative memory. Moreover, we demonstrated that an entorhinal-neocortical circuit underlies such neural plasticity, which will be helpful to understand the mechanisms of memory formation and retrieval in the brain.