Descending Post-commissural Fornix Lesions Produce Impaired Spatial Working Memory in a 12-arm Maze

Memory is supported in the brain by a distributed neural network, comprised of cortical, limbic and brainstem structures and fibre pathways. The descending component of the post-commissural fornix (dPCFx) conveys hippocampal efferents to the mammillary bodies (MB), and so presents as a critical pathway along the hippocampal-MB-anterior thalamic axis, structures all crucial to memory function. However, two previous studies have reported surprisingly mild, if any, effect of selective dPCFx lesions on spatial memory in an 8-arm radial arm maze (RAM). To examine the impact of dPCFx lesions on electrophysiological activity in the anterior thalamus, dorsal hippocampus and prefrontal cortex, and in an effort to substantially increase task difficulty, we trained rats postoperatively in a 12-arm RAM. We found that dPCFx lesions produced a severe RAM impairment, showing that the RAM can elicit spatial working memory deficits after dPCFx lesions when task demands are high and suggesting that the dPCFx may indeed play an important mnemonic role

Anterior thalamic nuclei neurons sustain memory

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis

Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson’s disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence

Optogenetic stimulation: understanding memory and treating deficits

Technology allowing genetically targeted cells to be modulated by light has revolutionized neuroscience in the past decade, and given rise to the field of optogenetic stimulation. For this, non‐native, light activated proteins (e.g., channelrhodopsin) are expressed in a specific cell phenotype (e.g., glutamatergic neurons) in a subset of central nervous system nuclei, and short pulses of light of a narrow wavelength (e.g., blue, 473 nm) are used to modulate cell activity. Cell activity can be increased or decreased depending on which light activated protein is used. We review how the greater precision provided by optogenetics has transformed the study of neural circuits, in terms of cognition and behavior, with a focus on learning and memory. We also explain how optogenetic modulation is facilitating a better understanding of the mechanistic underpinnings of some neurological and psychiatric conditions. Based on this research, we suggest that optogenetics may provide tools to improve memory in neurological conditions, particularly diencephalic amnesia and Alzheimer's disease

Optogenetic Stimulation of the Anterior Thalamic Nuclei Ameliorates Impaired Spatial Memory in Rats With Mammillothalamic Tract Lesions

Aims: Damage to the mammillothalamic tract (MTT) produces clinical amnesia and memory deficits in animal lesion models. These deficits reflect the loss of fibres terminating in the anterior thalamic nuclei (ATN) and thus impact the function of the extended memory system. We examined whether optogenetic stimulation of the glutamatergic ATN efferents would improve the behavioural and neural changes produced by MTT lesions. Methods: Rats with bilateral MTT lesions received viral vector (LV-CaMKIIa-ChR2 (H134R)-mCherry) infusions in the ATN. Spatial memory was tested using a 12-arm radial arm maze (RAM). The effects of no stimulation, optogenetic stimulation with blue light (465 nm; to activate channelrhodopsin) or orange light (620 nm; control condition) on memory performance were assessed using a counterbalanced design. Rats received regular or closed-loop theta burst stimulation (TBS) in the ATN at a frequency of 8.5 Hz. Results: Regular TBS with blue light produced a marked improvement in spatial memory performance in the MTT lesion group. No effects were found in any other stimulation conditions. TBS with blue light substantially increased neuronal activation in hippocampal CA1 and granular retrosplenial cortex, measured by zif268 immunohistochemistry. It also increased power spectral density in the ATN, hippocampus, and prefrontal cortex, plus ATN-hippocampal and ATN-prefrontal spectral coherence was also increased. Conclusions: Spatial memory deficits after MTT lesions can be ameliorated through selective optogenetic stimulation of the ATN. This recovery was associated with widespread neuronal changes in the extended hippocampus system that is important for memory function