Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning.

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories.

The Structure of Hippocampal CA1 Interactions Optimizes Spatial Coding across Experience.

Although much is known about how single neurons in the hippocampus represent an animal's position, how circuit interactions contribute to spatial coding is less well understood. Using a novel statistical estimator and theoretical modeling, both developed in the framework of maximum entropy models, we reveal highly structured CA1 cell-cell interactions in male rats during open field exploration. The statistics of these interactions depend on whether the animal is in a familiar or novel environment. In both conditions the circuit interactions optimize the encoding of spatial information, but for regimes that differ in the informativeness of their spatial inputs. This structure facilitates linear decodability, making the information easy to read out by downstream circuits. Overall, our findings suggest that the efficient coding hypothesis is not only applicable to individual neuron properties in the sensory periphery, but also to neural interactions in the central brain.SIGNIFICANCE STATEMENT Local circuit interactions play a key role in neural computation and are dynamically shaped by experience. However, measuring and assessing their effects during behavior remains a challenge. Here, we combine techniques from statistical physics and machine learning to develop new tools for determining the effects of local network interactions on neural population activity. This approach reveals highly structured local interactions between hippocampal neurons, which make the neural code more precise and easier to read out by downstream circuits, across different levels of experience. More generally, the novel combination of theory and data analysis in the framework of maximum entropy models enables traditional neural coding questions to be asked in naturalistic settings.

Theta oscillations as a substrate for medial prefrontal-hippocampal assembly interactions.

The execution of cognitive functions requires coordinated circuit activity across different brain areas that involves the associated firing of neuronal assemblies. Here, we tested the circuit mechanism behind assembly interactions between the hippocampus and the medial prefrontal cortex (mPFC) of adult rats by recording neuronal populations during a rule-switching task. We identified functionally coupled CA1-mPFC cells that synchronized their activity beyond that expected from common spatial coding or oscillatory firing. When such cell pairs fired together, the mPFC cell strongly phase locked to CA1 theta oscillations and maintained consistent theta firing phases, independent of the theta timing of their CA1 counterpart. These functionally connected CA1-mPFC cells formed interconnected assemblies. While firing together with their CA1 assembly partners, mPFC cells fired along specific theta sequences. Our results suggest that upregulated theta oscillatory firing of mPFC cells can signal transient interactions with specific CA1 assemblies, thus enabling distributed computations.

Replay of Behavioral Sequences in the Medial Prefrontal Cortex during Rule Switching.

Temporally organized reactivation of experiences during awake immobility periods is thought to underlie cognitive processes like planning and evaluation. While replay of trajectories is well established for the hippocampus, it is unclear whether the medial prefrontal cortex (mPFC) can reactivate sequential behavioral experiences in the awake state to support task execution. We simultaneously recorded from hippocampal and mPFC principal neurons in rats performing a mPFC-dependent rule-switching task on a plus maze. We found that mPFC neuronal activity encoded relative positions between the start and goal. During awake immobility periods, the mPFC replayed temporally organized sequences of these generalized positions, resembling entire spatial trajectories. The occurrence of mPFC trajectory replay positively correlated with rule-switching performance. However, hippocampal and mPFC trajectory replay occurred independently, indicating different functions. These results demonstrate that the mPFC can replay ordered activity patterns representing generalized locations and suggest that mPFC replay might have a role in flexible behavior. VIDEO ABSTRACT.

The entorhinal cognitive map is attracted to goals.

Grid cells with their rigid hexagonal firing fields are thought to provide an invariant metric to the hippocampal cognitive map, yet environmental geometrical features have recently been shown to distort the grid structure. Given that the hippocampal role goes beyond space, we tested the influence of nonspatial information on the grid organization. We trained rats to daily learn three new reward locations on a cheeseboard maze while recording from the medial entorhinal cortex and the hippocampal CA1 region. Many grid fields moved toward goal location, leading to long-lasting deformations of the entorhinal map. Therefore, distortions in the grid structure contribute to goal representation during both learning and recall, which demonstrates that grid cells participate in mnemonic coding and do not merely provide a simple metric of space.

Respiratory failure and spontaneous hypoglycemia during noninvasive rewarming from 24.7°C (76.5°F) core body temperature after prolonged avalanche burial.

Clinical reports on management and rewarming complications after prolonged avalanche burial are not common. We present a case of an unreported combination of respiratory failure and unexpected spontaneous hypoglycemia during noninvasive rewarming from severe hypothermia. We collected anecdotal observations in a 42-year-old, previously healthy, male backcountry skier admitted to the ICU at a tertiary care center after 2 hours 7 minutes of complete avalanche burial, who presented with a patent airway and a core body temperature of 25.0°C (77.0°F) on extrication. There was no decrease in core body temperature during transport (from 25.0°C [77.0°F] to 24.7°C [76.5°F]). Atrial fibrillation occurred during active noninvasive external rewarming (to 37.0°C [98.6°F] during 5 hours), followed by pulmonary edema and respiratory failure (SaO(2) 73% and PaO(2)/FIO(2) 161 mm Hg), which resolved with endotracheal intubation and continuous positive end-respiratory pressure. Moreover, a marked spontaneous glycemic imbalance (from 22.2 to 1.4 mmol/L) was observed. Despite a possible favorable outcome, clinicians should be prepared to identify and treat severe respiratory problems and spontaneous hypoglycemia during noninvasive rewarming of severely hypothermic avalanche victims.

Fatal cardiac arrest in an adult patient with euthyroid anti-SSA/Ro-positive connective tissue disease: a case report.

BACKGROUND: Until recently, anti-SSA/Ro antibodies were not considered pathogenic for severe heart disease in adults. Prolongation of the mean QTc interval in electrocardiograms of adult patients with anti-SSA/Ro-positive connective tissue disease has been reported and could contribute to complex arrhythmias in such patients. Furthermore, complete heart block may also be related to these autoantibodies. CASE PRESENTATION: We describe the occurrence of fatal complete heart block in a euthyroid adult patient with undifferentiated connective tissue disease and polyglandular autoimmune syndrome type 2 associated with cardiovascular autonomic dysfunction who had normal QTc interval. The patient's serum contained anti-SSA/Ro. CONCLUSION: This case might indicate that, although the adult heart conduction system may be relatively resistant to the development of anti-Ro-associated complete heart block, cardiac arrest may develop and even be fatal.