Mattia Maroso

Cannabinoid Control of Learning and Memory through HCN Channels

The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission

In the not too distant future, humankind will embark on one of its greatest adventures, the travel to distant planets. However, deep space travel is associated with an inevitable exposure to radiation fields. Space-relevant doses of protons elicit persistent disruptions in cognition and neuronal structure. However, whether space-relevant irradiation alters neurotransmission is unknown. Within the hippocampus, a brain region crucial for cognition, perisomatic inhibitory control of pyramidal cells (PCs) is supplied by two distinct cell types, the cannabinoid type 1 receptor (CB1)-expressing basket cells (CB1BCs) and parvalbumin (PV)-expressing interneurons (PVINs). Mice subjected to low-dose proton irradiation were analyzed using electrophysiological, biochemical and imaging techniques months after exposure. In irradiated mice, GABA release from CB1BCs onto PCs was dramatically increased. This effect was abolished by CB1 blockade, indicating that irradiation decreased CB1-dependent tonic inhibition of GABA release. These alterations in GABA release were accompanied by decreased levels of the major CB1 ligand 2-arachidonoylglycerol. In contrast, GABA release from PVINs was unchanged, and the excitatory connectivity from PCs to the interneurons also underwent cell type-specific alterations. These results demonstrate that energetic charged particles at space-relevant low doses elicit surprisingly selective long-term plasticity of synaptic microcircuits in the hippocampus. The magnitude and persistent nature of these alterations in synaptic function are consistent with the observed perturbations in cognitive performance after irradiation, while the high specificity of these changes indicates that it may be possible to develop targeted therapeutic interventions to decrease the risk of adverse events during interplanetary travel.

Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory

A way to prevent generalized seizures? Temporal lobe epilepsy is the most common form of epilepsy in adults. Patients have spontaneous seizures and risk developing serious cognitive impairment. Bui et al. studied an animal model of temporal lobe epilepsy (see the Perspective by Scharfman). Selective optogenetic inhibition of dentate gyrus mossy cells increased the likelihood of electrographic seizures generalizing to full behavioral convulsive seizures. Activation of mossy cells reduced the likelihood. Thus, the activity of mossy cells might serve to inhibit seizure propagation. Science, this issue p. 787; see also p. 740 There is a direct relationship between mossy cell activity in the dentate gyrus, convulsive seizures, and spatial memory formation in mice. Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.

Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice

ABSTRACT Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation‐induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1year after exposure. Cosmic‐radiation‐induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post‐irradiation intervals. HIGHLIGHTSLow dose cosmic irradiation causes significant adverse effects on CNS function.Functional CNS disruptions occur over times commensurate with a trip to Mars.Impairments to cognition and neural circuitry persisted 1year after exposure.Prolonged functional deficits were associated with elevated neuroinflammation.

Microcircuits in Epilepsy: Heterogeneity and Hub Cells in Network Synchronization

Epilepsy is a complex disorder involving neurological alterations that lead to the pathological development of spontaneous, recurrent seizures. For decades, seizures were thought to be largely repetitive, and had been examined at the macrocircuit level using electrophysiological recordings. However, research mapping the dynamics of large neuronal populations has revealed that seizures are not simply recurrent bursts of hypersynchrony. Instead, it is becoming clear that seizures involve a complex interplay of different neurons and circuits. Herein, we will review studies examining microcircuit changes that may underlie network hyperexcitability, discussing observations from network theory, computational modeling, and optogenetics. We will delve into the idea of hub cells as pathological centers for seizure activity, and will explore optogenetics as a novel avenue to target and treat pathological circuits. Finally, we will conclude with a discussion on future directions in the field.

Zika leaves a lasting impact on the brain

Zika Perinatal Zika virus (ZIKV) infection has been associated with brain alterations in newborns. However, whether ZIKV exposure during development has long-term neurological consequences is not completely understood. Nem de Oliveira Souza et al. report that newborn mice infected with ZIKV

Stroke therapy goes local

Stroke The complement system is activated by ischemic stroke to promote tissue repair. However, long-lasting systemic activation causes neurological impairments. Alawieh et al. show that specific local complement inhibition reduced cell death and inflammation and promoted functional recovery in a mouse model of stroke. Complement was targeted by linking a complement inhibitor to an antibody recognizing neoepitopes locally and transiently expressed in the ischemic area of the mouse brain. The targeted neoepitope was overexpressed in the ischemic region of brain tissue from stroke patients, indicating that the same approach might be effective in the clinic. Sci. Transl. Med. 10 , eaao6459 (2018).

Relieving pain with botox

Pain Chronic pain affects more than 25 million Americans and is associated with reduced life span, anxiety, and depression. Opioid administration is often effective in relieving pain but can cause severe side effects. Maiaru et al. leveraged the inhibitory effects of botulinum toxin on neuronal

Good vibrations for movement perception

Neurotechnology Because prostheses do not provide physical feedback during movement, amputees may not feel that they are in full control of their bodily action. Marasco et al. developed an automated neural-machine interface that vibrates the muscles used for the control of prosthetic hands. This system instilled kinesthetic sense in amputees, allowing them to control prosthetic hand movements in the absence of visual feedback and increasing their sense of control. Sci. Transl. Med. 10 , eaao6990 (2018).

Improving Huntington's disease detection

Huntingtons Disease Early detection of Huntingtons disease (HD) could help the development of therapeutic strategies to block or delay disease progression. Byrne et al. found that blood and cerebrospinal fluid concentrations of mutant huntingtin (mHTT) and neurofilament light (NfL) proteins correlated with disease severity in HD patients. Alterations in circulating mHTT and NfL concentrations were among the earliest detectable changes in HD. Thus, concentrations of these proteins in biofluids might be used in combination with other clinical measures for improving the accuracy and efficiency of early HD detection. Sci. Transl. Med. 10 , eaat7108 (2018).