Decision Making in Mice During an Optimized Touchscreen Spatial Working Memory Task Sensitive to Medial Prefrontal Cortex Inactivation and NMDA Receptor Hypofunction.

Working memory is a fundamental cognitive process for decision-making and is a hallmark impairment in a variety of neuropsychiatric and neurodegenerative diseases. Spatial working memory paradigms are a valuable tool to assess these processes in rodents and dissect the neurobiology underlying working memory. The trial unique non-match to location (TUNL) task is an automated touchscreen paradigm used to study spatial working memory and pattern separation processes in rodents. Here, animals must remember the spatial location of a stimulus presented on the screen over a delay period; and use this representation to respond to the novel location when the two are presented together. Because stimuli can be presented in a variety of spatial configurations, TUNL offers a trial-unique paradigm, which can aid in combating the development of unwanted mediating strategies. Here, we have optimized the TUNL protocol for mice to reduce training time and further reduce the potential development of mediating strategies. As a result, mice are able to accurately perform an enhanced trial-unique paradigm, where the locations of the sample and choice stimuli can be presented in any configuration on the screen during a single session. We also aimed to pharmacologically characterize this updated protocol, by assessing the roles of the medial prefrontal cortex (mPFC) and N-methyl-D-aspartate (NMDA) receptor (NMDAr) functioning during TUNL. Temporary inactivation of the medial prefrontal cortex (mPFC) was accomplished by directly infusing a mixture of GABA agonists muscimol and baclofen into the mPFC. We found that mPFC inactivation significantly impaired TUNL performance in a delay-dependent manner. In addition, mPFC inactivation significantly increased the susceptibility of mice to proactive interference. Mice were then challenged with acute systemic injections of the NMDAr antagonist ketamine, which resulted in a dose-dependent, delay-dependent working memory impairment. Together, we describe an optimized automated touchscreen task of working memory, which is dependent on the intact functioning of the mPFC and sensitive to acute NMDAr hypofunction. With the vast genetic toolbox available for modeling disease and probing neural circuit functioning in mice, the TUNL task offers a valuable paradigm to pair with these technologies to further investigate the processes underlying spatial working memory.

Basal Forebrain and Brainstem Cholinergic Neurons Differentially Impact Amygdala Circuits and Learning-Related Behavior.

The central cholinergic system and the amygdala are important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala, but it is unclear how these projections impact amygdala processes. Using optogenetic circuit-mapping strategies in choline acetyltransferase (ChAT)-cre mice, we demonstrate that amygdala-projecting basal forebrain and brainstem ChAT-containing neurons can differentially affect amygdala circuits and behavior. Photo-activating ChAT terminals in vitro revealed the underlying synaptic impact of brainstem inputs to the central lateral division to be excitatory, mediated via the synergistic glutamatergic activation of AMPA and NMDA receptors. In contrast, stimulating basal forebrain inputs to the basal nucleus resulted in endogenous acetylcholine (ACh) release, resulting in biphasic inhibition-excitation responses onto principal neurons. Such response profiles are physiological hallmarks of neural oscillations and could thus form the basis of ACh-mediated rhythmicity in amygdala networks. Consistent with this, in vivo basal forebrain ChAT+ activation strengthened amygdala basal nucleus theta and gamma frequency rhythmicity, both of which continued for seconds after stimulation and were dependent on local muscarinic and nicotinic receptor activation, respectively. Activation of brainstem ChAT-containing neurons, however, resulted in a transient increase in central lateral amygdala activity that was independent of cholinergic receptors. In addition, driving these respective inputs in behaving animals induced opposing appetitive and defensive learning-related behavioral changes. Because learning and memory are supported by both cellular and network-level processes in central cholinergic and amygdala networks, these results provide a route by which distinct cholinergic inputs can convey salient information to the amygdala and promote associative biophysical changes that underlie emotional memories.

Accumbal Cholinergic Interneurons Differentially Influence Motivation Related to Satiety Signaling.

Satiety, rather than all or none, can instead be viewed as a cumulative decrease in the drive to eat that develops over the course of a meal. The nucleus accumbens (NAc) is known to play a critical role in this type of value reappraisal, but the underlying circuits that influence such processes are unclear. Although NAc cholinergic interneurons (CINs) comprise only a small proportion of NAc neurons, their local impact on reward-based processes provides a candidate cell population for investigating the neural underpinnings of satiety. The present research therefore aimed to determine the role of NAc-CINs in motivation for food reinforcers in relation to satiety signaling. Through bidirectional control of CIN activity in mice, we show that when motivated by food restriction, increasing CIN activity led to a reduction in palatable food consumption while reducing CIN excitability enhanced food intake. These activity-dependent changes developed only late in the session and were unlikely to be driven by the innate reinforcer strength, suggesting that CIN modulation was instead impacting the cumulative change in motivation underlying satiety signaling. We propose that on a circuit level, an overall increase in inhibitory tone onto NAc output neurons played a role in the behavioral results, as activating NAc-CINs led to an inhibition of medium spiny neurons that was dependent on nicotinic receptor activation. Our results reveal an important role for NAc-CINs in controlling motivation for food intake and additionally provide a circuit-level framework for investigating the endogenous cholinergic circuits that signal satiety.

Perceptual deficits in amnesia: challenging the medial temporal lobe 'mnemonic' view.

Recent animal studies suggest that the medial temporal lobe (MTL), which is thought to subserve memory exclusively, may support non-mnemonic perceptual processes, with the hippocampus and perirhinal cortex contributing to spatial and object perception, respectively. There is, however, no support for this view in humans, with human MTL lesions causing prominent memory deficits in the context of apparently normal perception. We assessed visual discrimination in amnesic cases to reveal that while selective hippocampal damaged patients could discriminate faces, objects, abstract art and colour, they were significantly poorer in discriminating spatial scenes. By contrast, patients with MTL damage, including perirhinal cortex, were significantly impaired in discriminating scenes, faces, and to a lesser extent objects, with relatively intact discrimination of art and colour. These novel observations imply that the human MTL subserves both perceptual and mnemonic functions, with the hippocampus and perirhinal cortex playing distinct roles in spatial and object discrimination, respectively.