Optogenetic frequency scrambling of hippocampal theta oscillations dissociates working memory retrieval from hippocampal spatiotemporal codes.

The precise temporal coordination of activity in the brain is thought to be fundamental for memory function. Inhibitory neurons in the medial septum provide a prominent source of innervation to the hippocampus and play a major role in controlling hippocampal theta (~8 Hz) oscillations. While pharmacological inhibition of medial septal neurons is known to disrupt memory, the exact role of septal inhibitory neurons in regulating hippocampal representations and memory is not fully understood. Here, we dissociate the role of theta rhythms in spatiotemporal coding and memory using an all-optical interrogation and recording approach. We find that optogenetic frequency scrambling stimulations abolish theta oscillations and modulate a portion of neurons in the hippocampus. Such stimulation decreased episodic and working memory retrieval while leaving hippocampal spatiotemporal codes intact. Our study suggests that theta rhythms play an essential role in memory but may not be necessary for hippocampal spatiotemporal codes.

Conjunctive spatial and self-motion codes are topographically organized in the GABAergic cells of the lateral septum.

The hippocampal spatial code's relevance for downstream neuronal populations-particularly its major subcortical output the lateral septum (LS)-is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animal's location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior-posterior and dorsal-ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using transsynaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network.

Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits.

Reward-processing impairment is a common symptomatic dimension of several psychiatric disorders. However, whether the underlying pathological mechanisms are common is unknown. Herein, we asked if the decrease in the n-3 polyunsaturated fatty acid (PUFA) lipid species, consistently described in these pathologies, could underlie reward-processing deficits. We show that reduced n-3 PUFA biostatus in mice leads to selective motivational impairments. Electrophysiological recordings revealed increased collateral inhibition of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) onto dopamine D1 receptor-expressing MSNs in the nucleus accumbens, a main brain region for the modulation of motivation. Strikingly, transgenically preventing n-3 PUFA deficiency selectively in D2-expressing neurons normalizes MSN collateral inhibition and enhances motivation. These results constitute the first demonstration of a causal link between a behavioral deficit and n-3 PUFA decrease in a discrete neuronal population and suggest that lower n-3 PUFA biostatus in psychopathologies could participate in the etiology of reward-related symptoms.

Optogenetic gamma stimulation rescues memory impairments in an Alzheimer's disease mouse model.

Slow gamma oscillations (30-60 Hz) correlate with retrieval of spatial memory. Altered slow gamma oscillations have been observed in Alzheimer's disease. Here, we use the J20-APP AD mouse model that displays spatial memory loss as well as reduced slow gamma amplitude and phase-amplitude coupling to theta oscillations phase. To restore gamma oscillations in the hippocampus, we used optogenetics to activate medial septal parvalbumin neurons at different frequencies. We show that optogenetic stimulation of parvalbumin neurons at 40 Hz (but not 80 Hz) restores hippocampal slow gamma oscillations amplitude, and phase-amplitude coupling of the J20 AD mouse model. Restoration of slow gamma oscillations during retrieval rescued spatial memory in mice despite significant plaque deposition. These results support the role of slow gamma oscillations in memory and suggest that optogenetic stimulation of medial septal parvalbumin neurons at 40 Hz could provide a novel strategy for treating memory deficits in AD.

Gamma oscillations organize top-down signalling to hypothalamus and enable food seeking.

Both humans and animals seek primary rewards in the environment, even when such rewards do not correspond to current physiological needs. An example of this is a dissociation between food-seeking behaviour and metabolic needs, a notoriously difficult-to-treat symptom of eating disorders. Feeding relies on distinct cell groups in the hypothalamus, the activity of which also changes in anticipation of feeding onset. The hypothalamus receives strong descending inputs from the lateral septum, which is connected, in turn, with cortical networks, but cognitive regulation of feeding-related behaviours is not yet understood. Cortical cognitive processing involves gamma oscillations, which support memory, attention, cognitive flexibility and sensory responses. These functions contribute crucially to feeding behaviour by unknown neural mechanisms. Here we show that coordinated gamma (30-90 Hz) oscillations in the lateral hypothalamus and upstream brain regions organize food-seeking behaviour in mice. Gamma-rhythmic input to the lateral hypothalamus from somatostatin-positive lateral septum cells evokes food approach without affecting food intake. Inhibitory inputs from the lateral septum enable separate signalling by lateral hypothalamus neurons according to their feeding-related activity, making them fire at distinct phases of the gamma oscillation. Upstream, medial prefrontal cortical projections provide gamma-rhythmic inputs to the lateral septum; these inputs are causally associated with improved performance in a food-rewarded learning task. Overall, our work identifies a top-down pathway that uses gamma synchronization to guide the activity of subcortical networks and to regulate feeding behaviour by dynamic reorganization of functional cell groups in the hypothalamus.

Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring.

Environmental challenges to the maternal immune system during pregnancy have been associated with an increase in the frequency of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) appearing in the offspring. Microglia, the brain's resident immune-cells, are now known to be critically involved in normal brain development, shaping connections between neurons by pruning superfluous synaptic spines. Our aim was to investigate whether maternal infection during critical stages of gestation compromises the role of microglia in sculpting neuronal circuits. Using a mouse model of maternal immune activation (MIA) induced by bacterial Lipopolysaccharide (LPS), we assayed the offspring's behavior during postnatal development. Additionally, we quantified spines within the offspring's brain and assessed alterations in some molecular signals involved in pruning. LPS-induced MIA led to behavioral changes relevant to ASD in the offspring in the absence of gross neurological problems. Prenatal LPS resulted in a significant increase in the number of spines in the granule cells of the dentate gyrus, as well as a reduction in hippocampal expression of the fractalkine microglial receptor (CX3CR1), involved in mediating the pruning process in the offspring. Interestingly, these changes were only noted in the male progeny of the LPS challenged dams. These results provide an early indicator that microglial function is altered in the brain of offspring from immune challenged mothers and that the effects in the brain appear to be specific along sex lines.

Blunted Dopamine Transmission in Addiction: Potential Mechanisms and Implications for Behavior.

Positron emission tomography (PET) imaging consistently shows blunted striatal dopamine release and decreased dopamine D2 receptor availability in addiction. Here, we review the preclinical and clinical studies indicating that this neurobiological phenotype is likely to be both a consequence of chronic drug consumption and a vulnerability factor in the development of addiction. We propose that, behaviorally, blunted striatal dopamine transmission could reflect the increased impulsivity and altered cost/benefit computations that are associated with addiction. The factors that influence blunted striatal dopamine transmission in addiction are unknown. Herein, we give an overview of various factors, genetic, environmental, and social, that are known to affect dopamine transmission and that have been associated with the vulnerability to develop addiction. Altogether, these data suggest that blunted dopamine transmission and decreased D2 receptor availability are biomarkers both for the development of addiction and resistance to treatment. These findings support the view that blunted dopamine reflects impulsive behavior and deficits in motivation, which lead to the escalation of drug use.