Neural Substrates of Visual Perception and Working Memory: Two Sides of the Same Coin or Two Different Coins?

Visual perception occurs when a set of physical signals emanating from the environment enter the visual system and the brain interprets such signals as a percept. Visual working memory occurs when the brain produces and maintains a mental representation of a percept while the physical signals corresponding to that percept are not available. Early studies in humans and non-human primates demonstrated that lesions of the prefrontal cortex impair performance during visual working memory tasks but not during perceptual tasks. These studies attributed a fundamental role in working memory and a lesser role in visual perception to the prefrontal cortex. Indeed, single cell recording studies have found that neurons in the lateral prefrontal cortex of macaques encode working memory representations via persistent firing, validating the results of lesion studies. However, other studies have reported that neurons in some areas of the parietal and temporal lobe—classically associated with visual perception—similarly encode working memory representations via persistent firing. This prompted a line of enquiry about the role of the prefrontal and other associative cortices in working memory and perception. Here, we review evidence from single neuron studies in macaque monkeys examining working memory representations across different areas of the visual hierarchy and link them to studies examining the role of the same areas in visual perception. We conclude that neurons in early visual areas of both ventral (V1-V2-V4) and dorsal (V1-V3-MT) visual pathways of macaques mainly encode perceptual signals. On the other hand, areas downstream from V4 and MT contain subpopulations of neurons that encode both perceptual and/or working memory signals. Differences in cortical architecture (neuronal types, layer composition, and synaptic density and distribution) may be linked to the differential encoding of perceptual and working memory signals between early visual areas and higher association areas.

Learning differentially shapes prefrontal and hippocampal activity during classical conditioning

The ability to use sensory cues to inform goal directed actions is a critical component of behavior. To study how sounds guide anticipatory licking during classical conditioning, we employed high-density electrophysiological recordings from the hippocampal CA1 area and the prefrontal cortex (PFC) in mice. CA1 and PFC neurons undergo distinct learning dependent changes at the single cell level and maintain representations of cue identity at the population level. In addition, reactivation of task-related neuronal assemblies during hippocampal awake Sharp-Wave Ripples (aSWR) changed within individual sessions in CA1 and over the course of multiple sessions in PFC. Despite both areas being highly engaged and synchronized during the task, we found no evidence for coordinated single cell or assembly activity during conditioning trials or aSWR. Taken together, our findings support the notion that persistent firing and reactivation of task-related neural activity patterns in CA1 and PFC support learning during classical conditioning.

O037 Genioglossus motor control following the return to sleep after brief arousal

Rationale Arousal from sleep has been shown to elicit a prolonged increase in genioglossus muscle activity that persists following the return to sleep and may protect against airway collapse. We hypothesised that this increased genioglossal activity following return to sleep after an arousal is due to persistent firing of inspiratory single motor units (SMUs) recruited during the arousal. Methods 34 healthy participants were studied overnight while wearing a nasal mask/pneumotachograph to measure ventilation and with 4 intramuscular genioglossus SMU electrodes. During stable N2 and N3 sleep, auditory tones were played to induce brief (3-15s) AASM arousals. Ventilation and genioglossus SMUs were quantified for 5 breaths before the tone, during the arousal and for 10 breaths after the return to sleep. Results A total of 1089 tones were played and gave rise to 236 SMUs recorded across arousal and the return to sleep in 20 participants (age 23±4.2 years and BMI 22.5±2.2kg/m2). Ventilation was elevated above baseline during arousal and the first post-arousal breath (p<0.001). The peak firing frequency of expiratory and tonic SMUs was unchanged during arousal and return to sleep, whereas inspiratory modulated SMUs were increased during the arousal and for 4 breaths following the return to sleep (p<0.001). Conclusions The prolonged increase in genioglossus activity that occurs on return to sleep after arousal is a result of persistent activity of inspiratory SMUs. Strategies to elevate inspiratory genioglossus SMU activity may be beneficial in preventing/treating obstructive sleep apnea.

Locomotion induced by medial septal glutamatergic neurons is linked to intrinsically generated persistent firing

Medial septal glutamatergic neurons are active during theta oscillations and locomotor activity. Prolonged optogenetic activation of medial septal glutamatergic neurons drives theta oscillations and locomotion for extended periods of time outlasting the stimulus duration. However, the cellular and circuit mechanisms supporting the maintenance of both theta oscillations and locomotion remain elusive. Specifically, it remains unclear whether the presence of theta oscillations is a necessary prerequisite for locomotion, and whether neuronal activity within the medial septum underlies its persistence. Here we show that a persistent theta oscillation can be induced by a brief transient activation of glutamatergic neurons. Moreover, persistent locomotion is initiated even if the theta oscillation is abolished by blocking synaptic transmission in the medial septum. We observe persistent spiking of medial septal neurons that outlasts the stimulus for several seconds, both in vivo and in vitro. This persistent activity is driven by intrinsic excitability of glutamatergic neurons.

After-Discharge in the Upper Airway Muscle Genioglossus Following Brief Hypoxia

Study Objectives Genioglossus after-discharge is thought to protect against pharyngeal collapse by minimising periods of low upper airway muscle activity. How genioglossus after-discharge occurs and which single motor units (SMUs) are responsible for the phenomenon are unknown. The aim of this study was to investigate genioglossal after-discharge. Methods During wakefulness, after-discharge was elicited 8-12 times in healthy individuals with brief isocapnic hypoxia (45-60s of 10%O2 in N2) terminated by a single breath of 100% O2. Genioglossus SMUs were designated as firing solely, or at increased rate, during inspiration (Inspiratory phasic [IP] and inspiratory tonic [IT] respectively); solely, or at increased rate, during expiration (Expiratory phasic [EP] or expiratory tonic [ET] respectively) or firing constantly without respiratory modulation (Tonic). SMUs were quantified at baseline, the end of hypoxia, the hyperoxic breath and the following 8 normoxic breaths. Results 210 SMU’s were identified in 17 participants. Genioglossus muscle activity was elevated above baseline for 7 breaths after hyperoxia (p<0.001), indicating a strong after-discharge effect. After-discharge occurred due to persistent firing of IP and IT units that were recruited during hypoxia, with minimal changes in ET, EP or Tonic SMUs. The firing frequency of units that were already active changed minimally during hypoxia or the afterdischarge period (P>0.05). Conclusion That genioglossal after-discharge is almost entirely due to persistent firing of previously silent inspiratory SMUs provides insight into the mechanisms responsible for the phenomenon and supports the hypothesis that the inspiratory and expiratory/tonic motor units within the muscle have idiosyncratic functions.

Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes

Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion. PFC neurons generate top-down goals through recurrent excitatory connections on spines. This persistent firing is the foundation for higher cognition, including working memory, and abstract thought. However, exposure to acute uncontrollable stress drives high levels of catecholamine release in the PFC, which activates feedforward calcium-cAMP signaling pathways to open nearby potassium channels, rapidly weakening synaptic connectivity to reduce persistent firing. Chronic stress exposures can further exacerbate these signaling events leading to loss of spines and resulting in marked cognitive impairment. In this review, we discuss how stress signaling mechanisms can lead to spine loss, including changes to BDNF-mTORC1 signaling, calcium homeostasis, actin dynamics, and mitochondrial actions that engage glial removal of spines through inflammatory signaling. Stress signaling events may be amplified in PFC spines due to cAMP magnification of internal calcium release. As PFC dendritic spine loss is a feature of many cognitive disorders, understanding how stress affects the structure and function of the PFC will help to inform strategies for treatment and prevention.

Persistent firing in LEC III neurons is differentially modulated by learning and aging

Whether and how persistent firing in lateral entorhinal cortex layer III (LEC III) supports temporal associative learning is still unknown. In this study, persistent firing was evoked in vitro from LEC III neurons from young and aged rats that were behaviorally naive or trained on trace eyeblink conditioning. Persistent firing ability from neurons from behaviorally naive aged rats was lower compared to neurons from young rats. Neurons from learning impaired aged animals also exhibited reduced persistent firing capacity, which may contribute to aging-related learning impairments. Successful acquisition of the trace eyeblink task, however, increased persistent firing ability in both young and aged rats. These changes in persistent firing ability are due to changes to the afterdepolarization, which may in turn be modulated by the postburst afterhyperpolarization. Together, these data indicate that successful learning increases persistent firing ability and decreases in persistent firing ability contribute to learning impairments in aging.

Acetylcholine synergizes with netrin-1 to drive persistent firing in the entorhinal cortex

The ability of the mammalian brain to maintain spatial representations of external or internal information for short periods of time has been associated with sustained neuronal spiking and reverberatory neural network activity in the medial entorhinal cortex. Here, we show that cholinergic activation of muscarinic receptors on entorhinal cortical neurons mediates plasma membrane recruitment of the netrin-1 receptor deleted-in-colorectal cancer (DCC) to promote muscarinic receptor-mediated persistent firing. Conditional deletion of netrin-1 or DCC, which are required for synaptic plasticity, inhibits cholinergic persistent firing, and leads to deficits in spatial working memory. Together, these findings indicate that normal working memory function requires synergistic action of acetylcholine and netrin-1.