Santiago Canals

Erbb4 Deletion from Fast-Spiking Interneurons Causes Schizophrenia-like Phenotypes

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.

Avoiding catastrophic failure in correlated networks of networks

Connecting complex networks is known to exacerbate perturbations and lead to cascading failures, but natural networks of networks are surprisingly stable. A theory now proposes that network structure holds the key to understanding this paradox.

CBP is required for environmental enrichment‐induced neurogenesis and cognitive enhancement

The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CREB‐binding protein (CBP), a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long‐lasting systemic and behavioural adaptations to environmental enrichment (EE). Morphological and behavioural analyses demonstrated that EE ameliorates deficits associated to CBP deficiency. However, CBP‐deficient mice also showed a strong defect in environment‐induced neurogenesis and impaired EE‐mediated enhancement of spatial navigation and pattern separation ability. These defects correlated with an attenuation of the transcriptional programme induced in response to EE and with deficits in histone acetylation at the promoters of EE‐regulated, neurogenesis‐related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment‐induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP‐dependent transcriptional neuroadaptation as an important mediator of EE‐induced benefits, a finding with important implications for mental retardation therapeutics.

Functional MRI of long-term potentiation: imaging network plasticity

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond to, changes in the environment. Molecular and physiological changes at the cellular level as well as network interactions are required in order to encode a pattern of synaptic activity into a long-term memory. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology in rats, we have previously reported a functional remodelling of long-range hippocampal networks induced by long-term potentiation (LTP) of synaptic plasticity in the perforant pathway. Here, we present new results demonstrating an increased bilateral coupling in the hippocampus specifically supported by the mossy cell commissural/associational pathway in response to LTP. This fMRI-measured increase in bilateral connectivity is accompanied by potentiation of the corresponding polysynaptically evoked commissural potential in the contralateral dentate gyrus and depression of the inactive convergent commissural pathway to the ipsilateral dentate. We review these and previous findings in the broader context of memory consolidation.

Adult newborn neurons are involved in learning acquisition and long-term memory formation: The distinct demands on temporal neurogenesis of different cognitive tasks

There is evidence that adult hippocampal neurogenesis influences hippocampal function, although the role these neurons fulfill in learning and consolidation processes remains unclear. Using a novel fast X‐ray ablation protocol to deplete neurogenic cells, we demonstrate that immature adult hippocampal neurons are required for hippocampal learning and long‐term memory formation. Moreover, we found that long‐term memory formation in the object recognition and passive avoidance tests, two paradigms that involve circuits with distinct emotional components, had different temporal demands on hippocampal neurogenesis. These results reveal new and unexpected aspects of neurogenesis in cognitive processes.

Widespread Vestibular Activation of the Rodent Cortex

Much of our understanding of the neuronal mechanisms of spatial navigation is derived from chronic recordings in rodents in which head-direction, place, and grid cells have all been described. However, despite the proposed importance of self-reference information to these internal representations of space, their congruence with vestibular signaling remains unclear. Here we have undertaken brain-wide functional mapping using both fMRI and electrophysiological methods to directly determine the spatial extent, strength, and time course of vestibular signaling across the rat forebrain. We find distributed activity throughout thalamic, limbic, and particularly primary sensory cortical areas in addition to known head-direction pathways. We also observe activation of frontal regions, including infralimbic and cingulate cortices, indicating integration of vestibular information throughout functionally diverse cortical regions. These whole-brain activity maps therefore suggest a widespread contribution of vestibular signaling to a self-centered framework for multimodal sensorimotor integration in support of movement planning, execution, spatial navigation, and autonomic responses to gravito-inertial changes.

Neurophysiological, metabolic and cellular compartments that drive neurovascular coupling and neuroimaging signals

Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals.

Frequency-Dependent Gating of Hippocampal–Neocortical Interactions

How and where hippocampal-neocortical interactions required for memory formation take place is a major issue of current research. Using a combined in vivo functional magnetic resonance imaging/electrophysiology approach, we have investigated whether specific frequencies of CA3 neuronal activation, inducing different forms of short-term plasticity at CA1 synapses, contribute to differential activity propagation in brain-wide networks connected to the hippocampus. We report that localized activation of CA3 neurons in dorsal hippocampus produced activity propagation within the hippocampal formation, including the subiculum and entorhinal cortex, which increased monotonically with frequency to a maximum at 20-40 Hz. However, robust extrahippocampal propagation was seen specifically at theta-beta frequencies (10-20 Hz), reaching a network of midline neocortical and mesolimbic structures. Activation in those regions correlated with a frequency-dependent facilitation of spiking activity recorded in CA1. These results provide a mechanistic link between the dynamic properties of short-term plasticity in the efferent synapses of CA3 neurons in CA1 and activity propagation in brain-wide networks, and identify polysynaptic information channels segregated in the frequency domain.

Brain activation induced by voluntary alcohol and saccharin drinking in rats assessed with manganese-enhanced magnetic resonance imaging

The neuroanatomical and neurochemical basis of alcohol reward has been studied extensively, but global alterations of neural activity in reward circuits during chronic alcohol use remain poorly described. Here, we measured brain activity changes produced by long‐term voluntary alcohol drinking in the alcohol‐preferring AA (Alko alcohol) rats using manganese‐enhanced magnetic resonance imaging (MEMRI). MEMRI is based on the ability of paramagnetic manganese ions to accumulate in excitable neurons and thereby enhance the T1‐weighted signal in activated brain areas. Following 6 weeks of voluntary alcohol drinking, AA rats were allowed to drink alcohol for an additional week, during which they were administered manganese chloride (MnCl2) with subcutaneous osmotic minipumps before MEMRI. A second group with an identical alcohol drinking history received MnCl2 during the abstinence week following alcohol drinking. For comparing alcohol with a natural reinforcer, MEMRI was also performed in saccharin‐drinking rats. A water‐drinking group receiving MnCl2 served as a control. We found that alcohol drinking increased brain activity extensively in cortical and subcortical areas, including the mesocorticolimbic and nigrostriatal dopamine pathways and their afferents. Remarkably similar activation maps were seen after saccharin ingestion. Particularly in the prelimbic cortex, ventral hippocampus and subthalamic nucleus, activation persisted into early abstinence. These data show that voluntary alcohol recruits an extensive network that includes the ascending dopamine systems and their afferent connections, and that this network is largely shared with saccharin reward. The regions displaying persistent alterations after alcohol drinking could participate in brain networks underlying alcohol seeking and relapse.

Unsupervised segmentation of brain regions with similar microstructural properties: Application to alcoholism

In this work, a novel brain MRI segmentation approach evaluates microstructural differences between groups. Going further from the traditional segmentation of brain tissues (white matter -WM-, gray matter -GM- and cerebrospinal fluid -CSF- or a mixture of them), a new way to classify brain areas is proposed using their microstructural MR properties. Eight rats were studied using the proposed methodology identifying regions which present microstructural differences as a consequence on one month of hard alcohol consumption. Differences in relaxation times of the tissues have been found in different brain regions (p<;0.05). Furthermore, these changes allowed the automatic classification of the animals based on their drinking history (hit rate of 93.75 % of the cases).