Time-dependent involvement of the dorsal hippocampus in trace fear conditioning in mice

Hippocampal and amygdaloid neuroplasticity are important substrates for Pavlovian fear conditioning. The hippocampus has been implicated in trace fear conditioning. However, a systematic investigation of the significance of the trace interval has not yet been performed. Therefore, this study analyzed the time-dependent involvement of N-methyl-D-aspartate (NMDA) receptors in the dorsal hippocampus in one-trial auditory trace fear conditioning in C57BL/6J mice. The NMDA receptor antagonist APV was injected bilaterally into the dorsal hippocampus 15 min before training. Mice were exposed to tone (conditioned stimulus [CS]) and footshock (unconditioned stimulus [US]) in the conditioning context without delay (0 s) or with CS-US (trace) intervals of 1-45 s. Conditioned auditory fear was determined 24 h after training by the assessment of freezing and computerized evaluation of inactivity in a new context; 2 h later, context-dependent memory was tested in the conditioning context. NMDA receptor blockade by APV markedly impaired conditioned auditory fear at trace intervals of 15 s and 30 s, but not at shorter trace intervals. A 45-s trace interval prevented the formation of conditioned tone-dependent fear. Context-dependent memory was always impaired by APV treatment independent of the trace interval. The results indicate that the dorsal hippocampus and its NMDA receptors play an important role in auditory trace fear conditioning at trace intervals of 15-30-s length. In contrast, NMDA receptors in the dorsal hippocampus are unequivocally involved in contextual fear conditioning independent of the trace interval. The results point at a time-dependent role of the dorsal hippocampus in encoding of noncontingent explicit stimuli. Preprocessing of long CS-US contingencies in the hippocampus appears to be important for the final information processing and execution of fear memories through amygdala circuits.     

The stability of bilateral sagittal ramus osteotomy and vertical ramus osteotomy after bimaxillary correction of class III malocclusion

Introduction

The purpose of this retrospective cephalometric study was to compare the stability of bilateral sagittal split osteotomy (BSSO) with extra-oral vertical ramus osteotomy (VRO) after correction of class III malocclusion by means of bimaxillary orthognathic surgery.

Methods

The sample comprised 51 consecutively treated patients, 38 females and 13 males, with a mean age of 19.1 years. All had a one-piece Le Fort I osteotomy with maxillary advancement and mandibular setback. VRO was performed in 30 cases, and BSSO was performed in 21 cases. Lateral cephalograms were obtained before surgery, within 1 week of surgery and 1 year after surgery.

Results

The mean forward movement of the maxilla was 5.6 mm in both groups (p < 0.001). The mean horizontal surgical change in the VRO group was 4.4 mm (p < 0.001), and in the BSSO group it was 5.4 mm (p < 0.001). In the VRO group, the horizontal relapse was 1.2 mm (p < 0.001), and in the BSSO group, it was 1.4 mm (p < 0.001).

Conclusion

There was no difference in the stability between the BSSO and VRO groups. The average relapse in the whole sample was 26% of the surgical movement.     

Central 5-HT1A receptor-mediated modulation of heart rate dynamics and its adjustment by conditioned and unconditioned fear in mice

BACKGROUND AND PURPOSE

The beat-by-beat fluctuation (dynamics) of heart rate (HR) depends on centrally mediated control of the autonomic nervous system (ANS) reflecting the physiological state of an organism. 5-HT_1A receptors are implicated in affective disorders,associated with ANS dysregulation which increases cardiac risk but their role in autonomic HR regulation under physiological conditions is insufficiently characterized.

EXPERIMENTAL APPROACH

The effects of subcutaneously administered 5-HT_1A receptor ligands on HR dynamics were investigated in C57BL/6 mice during stress-free conditions and emotional challenge (recall of fear conditioned to an auditory stimulus and novelty exposure) using time domain and non-linear HR analyses.

KEY RESULTS

Pre-training treatment with of 8-OH-DPAT (0.5 mg·kg⁻¹, s.c.) prevented conditioned tachycardia in the retention test indicating impaired fear memory. Pretest 5-HT_1A receptor activation by 8-OH-DPAT (0.5 but not 0.1 and 0.02 mg·kg⁻¹) caused bradycardia and increased HR variability. 8-OH-DPAT (0.5 mg·kg⁻¹) lowered the unconditioned and conditioned tachycardia from ∼750 to ∼550 bpm, without changing the conditioned HR response to the sound. 8-OH-DPAT induced profound QT prolongation and bradyarrhythmic episodes. Non-linear analysis indicated a pathological state of HR dynamics after 8-OH-DPAT (0.5 mg·kg⁻¹) with ANS hyperactivation impairing HR adaptability. The 5-HT_1A receptor antagonist WAY-100635 (0.03 mg·kg⁻¹) blocked these effects of 8-OH-DPAT.

CONCLUSIONS AND IMPLICATIONS

Pre-training 5-HT_1A receptor activation by 8-OH-DPAT (0.5 mg·kg⁻¹) impaired memory of conditioned auditory fear based on an attenuated HR increase, whereas pretest administration did not prevent the fear-conditioned HR increase but induced pathological HR dynamics through central ANS dysregulation with cardiac effects similar to acute SSRI overdose.     

Microvascular blood flow changes of the abductor pollicis brevis muscle during sustained static exercise

A practical assessment of the general health and microvascular function of the palm muscle, abductor pollicis brevis (APB), is important for the diagnosis of different conditions. In this study, we have developed a protocol and a probe to study microvascular blood flow using near-infrared diffuse correlation spectroscopy (DCS) in APB during and after thumb abduction at 55% of maximum voluntary contraction (MVC). Near-infrared time resolved spectroscopy (TRS) was also used to characterize the baseline optical and hemodynamic properties. Thirteen (n=13) subjects were enrolled and subdivided in low MVC (N=6, MVC<2.3 kg) and high MVC (N=7, MVC≥2.3 kg) groups. After ruling out significant changes in the systemic physiology that influence the muscle hemodynamics, we have observed that the high MVC group showed a 56% and 36% decrease in the blood flow during exercise, with respect to baseline, in the long and short source-detector (SD) separations (p=0.031 for both). No statistical differences were shown for the low MVC group (p=1 for short and p=0.15 for long SD). These results suggest that the mechanical occlusion, due to increased intramuscular pressure, exceeded the vasodilation elicited by the higher metabolic demand. Also, blood flow changes during thumb contraction negatively correlated (R=-0.7, p<0.01) with the absolute force applied by each subject. Furthermore, after the exercise, muscular blood flow increased significantly immediately after thumb contractions in both high and low MVC groups, with respect to the recorded values during the exercise (p=0.031). An increase of 251% (200%) was found for the long (short) SD in the low MVC group. The high MVC groups showed a significant 90% increase in blood flow only after 80 s from the start of the protocol. For both low and high MVC groups, blood flow recovered to baseline values within 160 s from starting the exercise. In conclusion, DCS allows the study of the response of a small muscle to static exercise and can be potentially used in multiple clinical conditions scenarios for assessing microvascular health.     

“Atypical” neuromodulatory profile of glutapyrone, a representative of a novel `class'' of amino acid-containing dipeptide-mimicking 1,4-dihydropyridine (DHP) compounds: in vitro and in vivo studies

Glutapyrone, a disodium salt of 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)-glutaric acid, is a representative of a novel ‘class' of amino acid-containing 1,4-dihydropyridine (DHP) compounds developed at the Latvian Institute of Organic Synthesis, Riga, Latvia. Conceptually, the glutapyrone molecule can be regarded as a dipeptide-mimicking structure formed by the “free” amino acid (glutamate) moiety and “crypto” (built into the DHP cycle) amino acid (“GABA”) elements. Both of these amino acids are joined by the peptide bond. This compound unlike classical DHPs lacks calcium antagonistic or agonistic properties. Our previous studies revealed a profound and long-term anticonvulsant, stress-protective and neurodeficit-preventive activities of glutapyrone. In view of structural properties the role of glutamatergic mechanisms in the mediation of central effects of glutapyrone was considered. In the present study glutapyrone at the concentration range of 1 μM–1 mM failed to effect both NMDA ([³H]TCP) and non-NMDA ([³H]KA and [³H]AMPA) receptor ligand binding in the rat cortical membranes in vitro. The compound markedly enhanced motor hyperactivity induced by the NMDA antagonist PCP and the dopamine releasing compound -amphetamine in the rats. Glutapyrone displayed activity in a variety of animal models relevant for affective/depressive disorders in humans i.e. reserpine-induced ptosis and hypothermia, forced swimming test and open field test. These data indicate that the unusually “broad” pharmacological spectrum of glutapyrone might involve concomitant actions on multiple neurotransmitter systems, particularly, GABA-ergic and the catecholamines. It is discussed whether these functional properties are secondary to action on intracellular events, predominantly, G protein-related since glutapyrone appears to lack direct interactions with a number of receptors including ionotropic glutamate and GABA_A/Bzd receptors.