Dynamical Models in Neuroscience From a Closed-Loop Control Perspective.

Modifying neural activity is a substantial goal in neuroscience that facilitates the understanding of brain functions and the development of medical therapies. Neurobiological models play an essential role, contributing to the understanding of the underlying brain dynamics. In this context, control systems represent a fundamental tool to provide a correct articulation between model stimulus (system inputs) and outcomes (system outputs). However, throughout the literature there is a lack of discussions on neurobiological models, from the formal control perspective. In general, existing control proposals applied to this family of systems, are developed empirically, without theoretical and rigorous framework. Thus, the existing control solutions, present clear and significant limitations. The focus of this work is to survey dynamical neurobiological models that could serve for closed-loop control schemes or for simulation analysis. Consequently, this paper provides a comprehensive guide to discuss and analyze control-oriented neurobiological models. It also provides a potential framework to adequately tackle control problems that could modify the behavior of single neurons or networks. Thus, this study constitutes a key element in the upcoming discussions and studies regarding control methodologies applied to neurobiological systems, to extend the present research and understanding horizon for this field.

A novel role for the lateral habenula in fear learning.

Fear is an extreme form of aversion that underlies pathological conditions such as panic or phobias. Fear conditioning (FC) is the best-understood model of fear learning. In FC the context and a cue are independently associated with a threatening unconditioned stimulus (US). The lateral habenula (LHb) is a general encoder of aversion. However, its role in fear learning remains poorly understood. Here we studied in rats the role of the LHb in FC using optogenetics and pharmacological tools. We found that inhibition or activation of the LHb during entire FC training impaired both cued and contextual FC. In contrast, optogenetic inhibition of the LHb restricted to cue and US presentation impaired cued but not contextual FC. In either case, simultaneous activation of contextual and cued components of FC, by the presentation of the cue in the training context, recovered the conditioned fear response. Our results support the notion that the LHb is required for the formation of independent contextual and cued fear memories, a previously uncharacterized function for this structure, that could be critical in fear generalization.

Volume-Conducted Origin of the Field Potential at the Lateral Habenula.

Field potentials (FPs) are easily reached signals that provide information about the brain's processing. However, FP should be interpreted cautiously since their biophysical bases are complex. The lateral habenula (LHb) is a brain structure involved in the encoding of aversive motivational values. Previous work indicates that the activity of the LHb is relevant for hippocampal-dependent learning. Moreover, it has been proposed that the interaction of the LHb with the hippocampal network is evidenced by the synchronization of LHb and hippocampal FPs during theta rhythm. However, the origin of the habenular FP has not been analyzed. Hence, its validity as a measurement of LHb activity has not been proven. In this work, we used electrophysiological recordings in anesthetized rats and feed-forward modeling to investigate biophysical basis of the FP recorded in the LHb. Our results indicate that the FP in the LHb during theta rhythm is a volume-conducted signal from the hippocampus. This result highlight that FPs must be thoroughly analyzed before its biological interpretation and argues against the use of the habenular FP signal as a readout of the activity of the LHb.

Chronic pregabalin treatment decreases excitability of dentate gyrus and accelerates maturation of adult-born granule cells.

Pregabalin (PGB) is extensively prescribed to treat neurological and neuropsychiatrical conditions such as neuropathic pain, anxiety disorders, and epilepsy. Although PGB is known to bind selectively to the α2δ subunit of voltage-gated calcium channels, there is little understanding about how it exerts its therapeutic effects. In this article, we analyzed the effects of an in vivo chronic treatment with PGB over the physiology of dentate gyrus granule cells (DGGCs) using ex vivo electrophysiological and morphological analysis in adult mice. We found that PGB decreases neuronal excitability of DGGCs. In addition, PGB accelerates maturation of adult-born DGGCs, an effect that would modify dentate gyrus plasticity. Together, these findings suggest that PGB reduces activity in the dentate gyrus and modulates overall network plasticity, which might contribute to its therapeutic effects. Cover Image for this issue: doi: 10.1111/jnc.13783.

Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment.

The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that γ-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted toward reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior.

Lateral Habenula determines long-term storage of aversive memories.

The Lateral Habenula (LHb) is a small brain structure that codifies negative motivational value and has been related to major depression. It has been shown recently that LHb activation is sufficient to induce aversive associative learning; however the key question about whether LHb activation is required for an aversive memory to be formed has not been addressed. In this article we studied the function of the LHb in memory formation using the Inhibitory Avoidance task (IA). We found that LHb inactivation during IA training does not disrupt memory when assessed 24 h after, but abolishes it 7 days later, indicating that LHb activity during memory acquisition is not necessary for memory formation, but regulates its temporal stability. These effects suggest that LHb inactivation modifies subjective perception of the training experience.

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS.

Upon entry into the central nervous system (CNS), serum insulin-like growth factor-1 (IGF-I) modulates neuronal growth, survival, and excitability. Yet mechanisms that trigger IGF-I entry across the blood-brain barrier remain unclear. We show that neuronal activity elicited by electrical, sensory, or behavioral stimulation increases IGF-I input in activated regions. Entrance of serum IGF-I is triggered by diffusible messengers (i.e., ATP, arachidonic acid derivatives) released during neurovascular coupling. These messengers stimulate matrix metalloproteinase-9, leading to cleavage of the IGF binding protein-3 (IGFBP-3). Cleavage of IGFBP-3 allows the passage of serum IGF-I into the CNS through an interaction with the endothelial transporter lipoprotein related receptor 1. Activity-dependent entrance of serum IGF-I into the CNS may help to explain disparate observations such as proneurogenic effects of epilepsy, rehabilitatory effects of neural stimulation, and modulatory effects of blood flow on brain activity.

Serum insulin-like growth factor I and ischemic brain injury.

Serum insulin-like growth factor I (IGF-I), which is mostly produced by the liver, has recently been shown to have the unexpected ability to modulate normal brain function as well as brain response to injury. Moreover, serum IGF-I levels are modified in many brain diseases, including stroke. However, whether these modifications are related to the disease process remains uncertain. We now examined a potential relationship between serum IGF-I and ischemic brain injury after middle cerebral artery occlusion (MCAo) and reperfusion in mice with either high or low serum IGF-I levels prior to insult. Surprisingly, we found that chronic high serum IGF-I correlates with increased brain infarct size following MCAo, while low levels correlate with reduced lesion size. Immunocytochemistry and immunoblot analyses revealed that levels of phosphorylated (i.e., activated) MAPK, known to be associated with the severity of ischemic brain injury, were increased in IGF-I treated mice. No overall effect of IGF-I treatment on IGF family mRNA expression in the brain was observed. Altogether, these results indicate that serum IGF-I levels negatively correlate with stroke outcome. Therefore, lowering serum IGF-I levels in aging mammals, including humans, may be beneficial against the increased risk of stroke associated to old age.

Insulin and insulin-like growth factor I signalling in neurons.

Insulin-like peptides are an ancient acquisition in phylogeny, suggesting a crucial biological role for these family of peptides. Indeed, a key function of these hormones in cell metabolism and growth has been firmly established. However, their significance in neuronal physiology is less characterized, although progress in recent years on the neuroactive properties of insulin and insulin-like growth factor I (IGF-I) supports an important role for these hormones in brain function. During development, appropriate IGF-I input is critical in brain growth while the role of insulin at this stage, although not well defined yet, may be related to the control of neuronal survival. In the adult, IGF-I is a pleiotropic signal involved in numerous processes to maintain adequate brain cell functions, while the role of insulin is better known in relation to the control of food consumption and glucose metabolism. The potential involvement of IGF-I in brain diseases associated with neuronal death is strongly supported by its neuroprotective role. Further, the unexplained high incidence of glucose metabolism dysregulation in brain diseases makes also insulin a strong candidate in neuro-pathological research. Because mounting evidence suggests a complementary role of insulin and IGF-I in the brain, unveiling the cellular and molecular pathways involved in brain insulin/IGF-I actions is helping to establish potentially new therapeutic targets and its exploitation may lead to new treatments for a wide array of brain diseases.

Ca2+ channels and synaptic transmission at the adult, neonatal, and P/Q-type deficient neuromuscular junction.

Different types of voltage-activated Ca(2+) channels have been established based on their molecular structure and pharmacological and biophysical properties. One of them, the P/Q-type, is the main channel involved in nerve-evoked neurotransmitter release at neuromuscular junctions and the immunological target in Eaton-Lambert Syndrome. At adult neuromuscular junctions, L- and N-type Ca(2+) channels become involved in transmitter release only under certain experimental or pathological conditions. In contrast, at neonatal rat neuromuscular junctions, nerve-evoked synaptic transmission depends jointly on both N- and P/Q-type channels. Synaptic transmission at neuromuscular junctions of the ataxic P/Q-type Ca(2+) channel knockout mice is also dependent on two different types of channels, N- and R-type. At both neonatal and P/Q knockout junctions, the K(+)-evoked increase in miniature endplate potential frequency was not affected by N-type channel blockers, but strongly reduced by both P/Q- and R-type channel blockers. These differences could be accounted for by a differential location of the channels at the release site, being either P/Q- or R-type Ca(2+) channels located closer to the release site than N-type Ca(2+) channels. Thus, Ca(2+) channels may be recruited to mediate neurotransmitter release where P/Q-type channels seem to be the most suited type of Ca(2+) channel to mediate exocytosis at neuromuscular junctions.

Differential Ca2+-dependence of transmitter release mediated by P/Q- and N-type calcium channels at neonatal rat neuromuscular junctions.

N- and P/Q-type voltage dependent calcium channels (VDCCs) mediate transmitter release at neonatal rat neuromuscular junction (NMJ). Thus the neonatal NMJ allows an examination of the coupling of different subtypes of VDCCs to the release process at a single synapse. We studied calcium dependence of transmitter release mediated by each channel by blocking with omega-conotoxin GVIA the N-type channel or with omega-agatoxin IVA the P/Q-type channel while changing the extracellular calcium concentration ([Ca2+]o). Transmitter release mediated by P/Q-type VDCCs showed steeper calcium dependence than N-type mediated release (average slope 3.6 +/- 0.09 vs. 2.6 +/- 0.03, respectively). Loading the nerve terminals with 10 microm BAPTA-AM in the extracellular solution reduced transmitter release and occluded the blocking effect of omega-conotoxin GVIA (blockade -2 +/- 9%) without affecting the action of omega-agatoxin IVA (blockade 85 +/- 4%). Both VDCC blockers were able to reduce the amount of facilitation produced by double-pulse stimulation. In these conditions facilitation was restored by increasing [Ca2+]o. The facilitation index (fi) was also reduced by loading nerve terminals with 10 microm BAPTA-AM (fi = 1.2 +/- 0.1). The control fi was 2.5 +/- 0.1. These results show that P/Q-type VDCCs were more efficiently coupled to neurotransmitter release than were N-type VDCCs at the neonatal neuromuscular junction. This difference could be accounted for by a differential location of these channels at the release site. In addition, our results indicate that space-time overlapping of calcium domains was required for facilitation.