CA1 Long-Term Potentiation Is Diminished but Present in Hippocampal Slices from α-CaMKII Mutant Mice

Previous work has shown that mice missing the α-isoform of calcium–calmodulin-dependent protein kinase II (α-CaMKII) have a deficiency in CA1 hippocampal long-term potentiation (LTP). Follow-up studies on subsequent generations of these mutant mice in a novel inbred background by our laboratories have shown that whereas a deficiency in CA1 LTP is still present in α-CaMKII mutant mice, it is different both quantitatively and qualitatively from the deficiency first described. Mice of a mixed 129SvOla/SvJ;BALB/c;C57Bl/6 background derived from brother/sister mating of the α-CaMKII mutant line through multiple generations (>10) were produced by use of in vitro fertilization. Although LTP at 60 min post-tetanus was clearly deficient in these (−/−) α-CaMKII mice (42.6%, n=33) compared with (+/+) α-CaMKII control animals (81.7%, n=17), α-CaMKII mutant mice did show a significant level of LTP. The amount of LTP observed in α-CaMKII mutants was normally distributed, blocked by APV (2.7%, n=8), and did not correlate with age. Although this supports a role for α-CaMKII in CA1 LTP, it also suggests that a form of α-CaMKII-independent LTP is present in mice that could be dependent on another kinase, such as the β-isoform of CaMKII. A significant difference in input/output curves was also observed between (−/−) α-CaMKII and (+/+) α-CaMKII animals, suggesting that differences in synaptic transmission may be contributing to the LTP deficit in mutant mice. However, tetani of increasing frequency (50, 100, and 200 Hz) did not reveal a higher threshold for potentiation in (−/−) α-CaMKII mice compared with (+/+) α-CaMKII controls.     

α7 Nicotinic Receptor Subunits Are Not Necessary for Hippocampal-Dependent Learning or Sensorimotor Gating: A Behavioral Characterization of Acra7-Deficient Mice

The α7 nicotinic acetylcholine receptor (nAChR) subunit is abundantly expressed in the hippocampus and contributes to hippocampal cholinergic synaptic transmission suggesting that it may contribute to learning and memory. There is also evidence for an association between levels of α7 nAChR and in sensorimotor gating impairments. To examine the role of α7 nAChRs in learning and memory and sensorimotor gating, Acra7 homozygous mutant mice and their wild-type littermates were tested in a Pavlovian conditioned fear test, for spatial learning in the Morris water task, and in the prepulse inhibition paradigm. Exploratory activity, motor coordination, and startle habituation were also evaluated. Acra7 mutant mice displayed the same levels of contextual and auditory-cue condition fear as wild-type mice. Similarly, there were no differences in spatial learning performance between mutant and wild-type mice. Finally, Acra7 mutant and wild-type mice displayed similar levels of prepulse inhibition. Other behavioral responses in Acra7 mutant mice were also normal, except for an anxiety-related behavior in the open-field test. The results of this study show that the absence of α7 nAChRs has little impact on normal, base-line behavioral responses. Future studies will examine the contribution of α7 nAChR to the enhancement of learning and sensorimotor gating following nicotine treatments.     

Impaired Learning and Motor Behavior in Heterozygous Pafah1b1 (Lis1) Mutant Mice

Heterozygous mutation or deletion of Pafah1b1 (LIS1) in humans is associated with syndromes with type 1 lissencephaly, a severe brain developmental disorder resulting from abnormal neuronal migration. We have created Lis1 heterozygous mutant mice by gene targeting. Heterozygous mutant mice are viable and fertile, but display global organizational brain defects as a result of impaired neuronal migration. To assess the functional impact of the mutation, Lis1 heterozygous mice and their wild-type littermates were evaluated on a wide variety of behavioral tests. Lis1 mutant mice displayed abnormal hindpaw clutching responses and were impaired on a rotarod test. Lis1 heterozygous mice were also impaired in the spatial learning version of the Morris water task. Impaired motor behavior and spatial learning and memory in Lis1 mutant mice indicates that impaired neuronal migration can have functional effects on complex behavioral responses. The behavioral findings also support the use of the Lis1 mutant mice as a model from human type 1 lissencephaly.     

Reduced K+ Channel Inactivation, Spike Broadening, and After-Hyperpolarization in Kvβ1.1-Deficient Mice with Impaired Learning

A-type K⁺ channels are known to regulate neuronal firing, but their role in repetitive firing and learning in mammals is not well characterized. To determine the contribution of the auxiliary K⁺ channel subunit Kvβ1.1 to A-type K⁺ currents and to study the physiological role of A-type K⁺ channels in repetitive firing and learning, we deleted the Kvβ1.1 gene in mice. The loss of Kvβ1.1 resulted in a reduced K⁺ current inactivation in hippocampal CA1 pyramidal neurons. Furthermore, in the mutant neurons, frequency-dependent spike broadening and the slow afterhyperpolarization (sAHP) were reduced. This suggests that Kvβ1.1-dependent A-type K⁺ channels contribute to frequency-dependent spike broadening and may regulate the sAHP by controlling Ca²⁺ influx during action potentials. The Kvβ1.1-deficient mice showed normal synaptic plasticity but were impaired in the learning of a water maze test and in the social transmission of food preference task, indicating that the Kvβ1.1 subunit contributes to certain types of learning and memory.     

Consolidation of Memory for Odor–Reward Association: β-Adrenergic Receptor Involvement in the Late Phase

Experimentally naive rats can learn rapidly to discriminate among three odors to obtain food reinforcement. After three massed trials, they show almost errorless performance. This task has proved to be useful in studying time-dependent postacquisition intracellular processes necessary for long-term memory. The present experiments evaluated the temporal dynamics of the role of β-noradrenergic receptors in long-term consolidation. Rats were implanted with intracerebroventricular cannulae and trained in a single session to find reinforcement in a hole in a sponge impregnated with a particular odor. Injections of the β-receptor antagonist timolol were made at 5 min, 1, 2, or 5 hr after training. Memory and relearning ability were evaluated 48 hr later. Rats treated with timolol 2 hr after training showed a memory deficit at the retention test, but were able to relearn the task normally. Injections at the earlier or later time points were ineffective. The results reinforce previous observations with systemic injections that β-noradrenergic receptors are involved in the late phase of memory consolidation and suggest a critical time window during which they are necessary. The time window is compatible with the current view that long-term memory depends on late involvement of the cAMP cascade leading to new protein synthesis necessary for synaptic reorganization.     

TGF-β1 in Aplysia: Role in Long-Term Changes in the Excitability of Sensory Neurons and Distribution of TβR-II-Like Immunoreactivity

Exogenous recombinant human transforming growth factor β-1 (TGF-β1) induced long-term facilitation of Aplysia sensory-motor synapses. In addition, 5-HT-induced facilitation was blocked by application of a soluble fragment of the extracellular portion of the TGF-β1 type II receptor (TβR-II), which presumably acted by scavenging an endogenous TGF-β1-like molecule. Because TβR-II is essential for transmembrane signaling by TGF-β, we sought to determine whether Aplysia tissues contained TβR-II and specifically, whether neurons expressed the receptor. Western blot analysis of Aplysia tissue extracts demonstrated the presence of a TβR-II-immunoreactive protein in several tissue types. The expression and distribution of TβR-II-immunoreactive proteins in the central nervous system was examined by immunohistochemistry to elucidate sites that may be responsive to TGF-β1 and thus may play a role in synaptic plasticity. Sensory neurons in the ventral–caudal cluster of the pleural ganglion were immunoreactive for TβR-II, as well as many neurons in the pedal, abdominal, buccal, and cerebral ganglia. Sensory neurons cultured in isolation and cocultured sensory and motor neurons were also immunoreactive. TGF-β1 affected the biophysical properties of cultured sensory neurons, inducing an increase of excitability that persisted for at least 48 hr. Furthermore, exposure to TGF-β1 resulted in a reduction in the firing threshold of sensory neurons. These results provide further support for the hypothesis that TGF-β1 plays a role in long-term synaptic plasticity in Aplysia.     

Positive Correlation Between Serum Interleukin‐1β and State Anger in Rugby Athletes

Recently, several studies reported a relationship between immune system activation and anger expression. Consequently, the aim of this study was to explore immunitary molecular mechanisms that potentially underlie anger expression. To this end, we applied the Frustration—Aggression Theory in a contact sport model, utilizing the nearing of sporting events to trigger anger feelings. In parallel, we evaluated the activation of immune system at mRNA levels. We enrolled 20 amateur rugby players (age ± SD, 27.2 ± 4.5) who underwent psychological assessment to evaluate anger, with the State‐Trait Anger Expression Inventory‐2 (STAXI‐2), before rugby matches; at the same time blood samples were taken to analyze the variations of gene expression by microarray. During the 2 hr before each game, a significant increase was verified in the Rage State (RS) score compared to the score ascertained 72 hr before. At the same time, we found modulation in expression profile, in particular increased expression of gene that encodes interleukin l‐β (IL‐1β). In a regression analysis, RS score was related to IL‐1β, and the potential risk factors age, body mass index, smoking, and drinking. The levels of cytokine were positively and independently related to RS score. Our results suggest that the nearing of sporting event can trigger anger state feelings and activate immune system in rugby players. We propose the IL‐1β as a potential biological marker of anger. However, further research is necessary to clarify the correlation between cytokine and anger. Aggr. Behav. 39 :141‐148, 2013. © 2012 Wiley Periodicals, Inc.     

Two-flash threshold, sensitivity and β in normal subjects and schizophrenics

Two-flash threshold, response criterion, and sensitivity (defined by the slope of the psychophysical ogive), were examined in schizophrenics and in normals under three conditions--a base-line condition, and during and after continuous white noise. Schizophrenics were subdivided into four groups on the basis of whether or not they exhibited paranoid symptomatology and electrodermal orienting responses. In general schizophrenics had more lenient two-flash response criteria than normal subjects. In the base-line condition schizophrenics with orienting responses had lower two-flash thresholds than those without orienting responses. Paranoid schizophrenics had more lenient criteria than non-paranoid schizophrenics and lower sensitivity than the non-paranoid group with orienting responses. Differential group effects were obtained during and after noise, especially with regard to sensitivity.     

Why not to be a ‘Thomist’: A Critique of the Bañezian Reconciliation of Divine Foreknowledge and Human Freedom

Thomas Osborne has asserted that ‘No one has developed an argument against premotion that works if the distinctions made by the Thomists are granted.' This article attempts to form just such an argument. Specifically, it argues that the Thomistic system – even with the distinctions it relies on having been granted – cannot account for human freedom, at least not in a sense sufficiently strong to sustain human guilt for sin. Further, it argues that the Thomists, by their own clear though tacit admission, acknowledge this insufficiency.     

‘Bound in a nutshell’: Thoughts on complexity,reductionism, and ‘infinite space’1

Pluralism is the hallmark of 21st century psychoanalytic discourse. Nevertheless, an unpleasant byproduct of pluralism is a tendency in some quarters to retreat into orthodoxy, stemming from a perceived need to shore up theoretical boundaries in the service of differentiating one theory from another. The delineation of borders places us at a risk of losing sight of the fact that genuine psychoanalytic thinking is fundamentally non‐reductionistic. Moreover, the core psychoanalytic notion of overdetermination, which Freud never abandoned throughout his career, has recently been neglected as authors argue in their communications that one point of view is better than another. Both analysts and their patients secretly are drawn to simple formulations that eschew complexity. The need to remain open to the ‘infinite space’ of meaning, motive, and causation should be a hallmark of clinical psychoanalytic practice. The author considers the implications for technique, and provides case material to illustrate some of the challenges inherent in approaching psychoanalytic work as a complex phenomenon.